On April 21, 1992, Guillén suffered a severe knee injury in a collision with outfielder Tim Raines. The injury caused him to miss almost the entire season, and subsequently diminished his defensive range as well as his stolen base output for the remainder of his career. Guillén recovered in 1993 with his most productive season offensively, posting a .280 batting average, and career highs with 4 home runs and 50 runs batted in, as the White Sox won the American League Western Division title. He hit .273 and scored 4 runs in a losing effort, as the White Sox were defeated by the Toronto Blue Jays in the 1993 American League Championship Series.