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In his club career that started in 1987, Simeone played for Vélez Sarsfield, Pisa, Sevilla FC, Atletico Madrid, Inter Milan, and Lazio. He ended his playing career for Racing Club, playing his last match on 17 February 2006, and then becoming manager for the same team. After a rough start, the team made an impressive finish in the 2006 Clausura, but the pressure was too much for Simeone to handle, and on May 2006 he left Racing and was replaced with Reinaldo Merlo. On May 18, he was signed by Estudiantes de La Plata.
For the Argentine team, Simeone, nicknamed El Cholo after another player with the same surname, amassed 106 caps, the first coming in 1988. He played in the 1994, 1998 and 2002World Cups. In spite of being a defensive player, Simeone has scored 11 goals for his country. He was considered a great leader on the pitch. He was also a member of the team that won the silver medal at the 1996 Summer Olympics in Atlanta, Georgia.
During the 1998 Cup that he was part of an incident with David Beckham; the English star kicked Simeone and was sent off; Simeone responded verbally to Beckham's foul, to which the Englishman reacted (see also Argentina and England football rivalry).
An intimidating figure on the pitch, Simeone is humble off it, admitting to being "embarrassed" to surpass Diego Maradona as Argentina's most capped player.