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The friendly against La Celeste (the Sky Blue) at St. Louis comes four days after the Americans entertain Mexico, a 1-0 final winner earlier this month in the North American tournament, in a friendly rematch at East Rutherford, New Jersey.
Fifth-ranked Uruguay's top lineup includes such stars as Luis Suarez of Barcelona and Edinson Cavani of Paris Saint-Germain, who have combined for 106 goals for the national squad, which reached the quarter-finals of last year's World Cup before falling to eventual champion France.
"We look forward to this challenge against an excellent Uruguayan team," US coach Gregg Berhalter said.
Berhalter is 8-3 with one drawn since taking over the US squad last December in the wake of a major federation shakeup after the Americans failed to qualify for the 2018 World Cup.
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The Americans have not faced La Celeste since a 2-1 friendly victory at Washington in 2002 in a World Cup tuneup ahead of a last-eight run in South Korea. The rivalry is level at 2-2-2.