His time at United was successful, winning the Premier League, FA Cup, Football League Cup and FA Community Shield, along with winning the Sir Matt Busby Player of the Year twice. Van Nistelrooy hit 150 goals in just 219 games for United, as well as becoming, at the time, their all-time European record goalscorer, but fell out of favour towards the end of his tenure. Real Madrid then secured his services in 2006. Although an injury blighted the end of his days with Madrid, he won La Liga twice and the Supercopa de España before signing for Hamburger SV during the January transfer window in 2010. After one-and-a-half seasons with Hamburg, he moved back to Spain with Málaga in the summer of 2011. His retirement from football was announced on 14 May 2012.

Internationally, Van Nistelrooy represented the Netherlands on 70 occasions, netting 35 times. He was part of the Euro 2004, 2006 World Cup and Euro 2008 squads.

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Early career

Born in Oss, North Brabant, Van Nistelrooy started his career in 1993, aged 17, with Dutch Eerste Divisie side Den Bosch, where he was converted from a central midfielder to centre-forward, after playing for local clubs Nooit Gedacht and RKSV Margriet. After netting 12 goals in 31 games in the 1996–97 campaign, he transferred for €360,000 to Heerenveen the next year, and scored 13 goals in 31 matches in his only season with the club. He was then signed by PSV Eindhoven the next season for €6.3 million, a then-record transfer sum between two Dutch teams.

He scored 31 goals in 34 matches, the highest season total in the Eredivisie and second-highest in Europe overall, in addition to scoring all three of PSV's goals in a Champions League match against HJK Helsinki on 25 November 1998. Van Nistelrooy capped off the year by winning the Dutch Player of the Year award. The following season, he won his second Eredivisie scoring title with 29 goals.According to a 2001 interview with The Daily Telegraph, Manchester United coach Sir Alex Ferguson said that his son, Darren, who was at try-outs for Eredivisie rival Heerenveen at the time, begged his father, "You've got to sign Van Nistelrooy right away, he's fantastic. We've been watching him." Ferguson sent team representatives to PSV's next league game and signed Van Nistelrooy the next day.

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Manchester United

Van Nistelrooy looked set to complete a club record £18.5 million transfer to Manchester United in the summer of 2000.[ He was to be unveiled at a press conference four days later, but this was instead used to announce that the transfer had been postponed over concerns about his fitness, having not played for a month due to problems with his knee. The transfer was then cancelled after PSV refused to agree to further medical tests, and the next day he suffered a rupture to his anterior cruciate knee ligaments during a training session, leaving him injured for a year.

A year later, Van Nistelrooy signed a five-year contract after passing his medical. He downplayed United's £19 million investment to reporters, saying, "The price is not heavy for me – it lifts me up because it means United have big confidence in me."

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2001–02

Van Nistelrooy made his debut in the Charity Shield against Liverpool, scoring in a 2–1 loss. On 19 August, Van Nistelrooy made his Premier League debut against Fulham at Old Trafford, and scored two goals to help United to a 3–2 win. He scored his first Champions League goals on 17 October in a 3–2 loss to Deportivo La Coruña.

On 22 December, Van Nistelrooy scored his first Premier League hat-trick in a 6–1 win against Southampton. In the FA Cup, Van Nistelrooy started on the bench for the third round tie against Aston Villa due to a groin strain, but was substituted on for Luke Chadwick in the second-half with United 2–0 down and scored two "sublime" goals in three minutes to help United advance to the fourth round with a 3–2 win.

In total during his first season, Van Nistelrooy scored 23 goals in 32 league games. He broke the record he shared with Mark Stein, Alan Shearer and Thierry Henry, by scoring in eight consecutive league games. He also scored ten Champions League goals, and was named the PFA Players' Player of the Year.

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2002–03

The following season, he finished as the top Premier League scorer with 25 goals in 34 games, with a goal on the final day against Everton earning him the Golden Boot ahead of Arsenal's Thierry Henry. His tally included three hat-tricks against Newcastle United, Fulham, and Charlton Athletic. He also scored in each of the final eight games of the season as United won the title. Van Nistelrooy won the Premier League Player of the Season in 2003. He was accredited with spearheading the title win for United with a goal tally that was described as "astonishing". After scoring 12 Champions League goals, he was named by UEFA as the best striker in Europe.

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2003–04

Van Nistelrooy started the 2003–04 season by scoring twice in his first two league matches. This meant he had scored in 10 consecutive league games, then a Premier League record, which stood until 2015 when Jamie Vardy scored in 11 consecutive matches. In the 0–0 draw on 21 September 2003, later dubbed the Battle of Old Trafford, Van Nistelrooy was at the centre of one of the most infamous incidents of the Arsenal–Manchester United rivalry. After missing a last-minute penalty that would have won the game for United, Van Nistelrooy was attacked by Martin Keown, prompting a melee involving several players from both sides; five Arsenal players including Keown received various bans and fines, while the club itself received a record fine of £175,000. Earlier in the game, he had been fouled by Patrick Vieira, who was sent off for a second bookable offence. Vieira and his manager Arsène Wenger both accused Van Nistelrooy of cheating and stamping on Vieira, prompting a vociferous defence by Alex Ferguson.

On 27 September, he scored a hat-trick against Leicester City in a 4–1 victory. He scored his 100th goal for the club in a dramatic 4–3 victory over Everton on 7 February 2004.

In the FA Cup fifth round derby against Manchester City, Van Nistelrooy scored twice to help ten-man United win 4–2, and again scored twice in the quarter-final against Fulham as United came from behind to win 2–1. He scored a further two goals, including one penalty, in United's victory over Millwall in the 2004 FA Cup Final.

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2004–05

Van Nistelrooy missed a large part of the 2004–05 season due to injury, but nonetheless scored a Champions League-best eight goals. One of them was his 30th career European goal, which he scored in a 2–2 Champions League group stage draw with Lyon on 16 September 2004, overtaking Denis Law's previous club record of 28 goals. Law later said to reporters, "I'm delighted for Ruud. It could not happen to a nicer guy."

On 24 October, Arsenal returned to Old Trafford for another dramatic fixture. Arsenal entered the fixture with 49-game unbeaten run and had been dubbed "The Invincibles", but United won the game 2–0. Van Nistelrooy scored the opening goal from the penalty spot, atoning for the penalty miss the previous year, with Wayne Rooney scoring a second. Van Nistelrooy was later banned for three games for a foul on Ashley Cole that the referee had missed. On 3 November, Van Nistelrooy scored all four goals in a 4–1 win against Sparta Prague. On 17 April 2005, he scored two goals in the FA Cup semi-final in a 4–1 win against Newcastle, but United lost the final on penalties to Arsenal.

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2005–06

At the start of the 2005–06 season, Van Nistelrooy scored in United's first four Premier League games. He finished as the second-highest league scorer with 21 goals, behind Arsenal's Thierry Henry. However, he was benched for the League Cup Final against Wigan Athletic, fuelling speculation of a rift between him and Alex Ferguson, which Van Nistelrooy denied. He was nonetheless left on the bench for six consecutive league matches, and though he then returned to the starting line-up and scored match-winners against West Ham United and Bolton Wanderers, fresh doubt spread over Van Nistelrooy's future when he was benched for United's season finale win over Charlton Athletic. Ferguson claimed that Van Nistelrooy was angry at the decision and left the stadium three hours before kick-off. On 9 May 2006, it was reported that Van Nistelrooy's exclusion from the squad was due to a training session fight between him and teammate Cristiano Ronaldo. Van Nistelrooy allegedly criticised Ronaldo's tendency to hold onto the ball instead of passing to his teammates, which sparked the fight, after which Van Nistelrooy remarked, "Go crying to your daddy," which was in reference to United's Portuguese assistant manager, Carlos Queiroz. Ronaldo, however, took the statement literally and allegedly broke into tears since his father José had died eight months previously. Van Nistelrooy later apologised to Ferguson for his behaviour in the previous few months.

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Van Nistelrooy signed with Spanish La Liga side Real Madrid on 28 July, departing Old Trafford after five seasons with a total of 150 goals in 219 appearances, with his final goal coming on 1 April against Bolton, scoring what proved to be the winning goal. With 38 goals, he is also the club's second all-time European goalscorer, behind Wayne Rooney.