Javier Vázquez went against Johan Santana, who pitched so well in Game 1. The Twins were on the board first with a sacrifice fly by Torii Hunter. But the Yankees would tie it on an RBI single by Hideki Matsui in the third. Another sac fly untied the score and gave the Twins the lead back in the fourth. Henry Blanco led the bottom of the fifth off with a home run to make it 3–1 Twins. A two-run double by Lew Ford extended the Twins' lead to 5–1 later in the inning. However, the Twins would squander the lead in the top of the eighth with Juan Rincón pitching in relief. Bernie Williams would single home Gary Sheffield after a single and wild pitch. With Matsui and Williams on base and one out, Rubén Sierra hit the game-tying three-run home run to make it tied at five. Joe Nathan would come on in relief and get the next two outs. But, once again, the Twins blew the lead and a sense of déjà vu hung in the air. When the game moved to extra innings, Mariano Rivera came on and shut the Twins down. But the series would end when Alex Rodriguez doubled, stole third, and scored on Kyle Lohse's wild pitch in the top of the eleventh. Rivera would get the win as he retired the Twins 1–2–3 to end the series in the bottom of the eleventh.
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