U.S. midfielder Jermaine Jones will miss Tuesday's game with Mexico at the Azteca Stadium due to a left ankle sprain, a team spokesman said on Sunday.
Jones suffered the injury in Friday's 1-0 win over Costa Rica in Denver.
The German-born player was an immense presence in midfield in the snow-plagued game, setting the tone with his hard running and tackling.
Maurice Edu is the most likely replacement for Jones.
The United States, who have three points from two games, have never beat Mexico at the Azteca in a qualifier.