Fifth seed Nikolay Davydenko became the first major casualty at the Cincinnati Masters when he lost 6-4, 2-6, 6-2 to Argentine Juan Ignacio Chela in the opening round.
But number six James Blake led an American hat-trick of opening victories as he defeated Fabrice Santoro 6-4, 6-4 on a bad day for France on Saturday.
Robby Ginepri and former finalist Mardy Fish followed suit for the US, with the 15th-seeded Ginepri eliminating another French opponent in Paul-Henri Mathieu 1-6, 6-3, 6-4.
Wildcard Fish, losing finalist in 2003 to Andy Roddick, outclassed Nicolas Mahut of France 6-1, 6-3.
Argentine Chela handed Russia's Davydenko a second consecutive first-round hardcourt defeat in the wake of a clay title won last month at Sopot, Poland.
The marathon man has played in 24 of a possible 25 tournaments this season, registering a 44-22 record.
Chela, who broke his opponent four times, now meets Vince Spadea of the US or Italian Andreas Seppi.
Third seed David Nalbandian swept past South African qualifier Rik De Voest 6-0, 6-4 despite rain interruptions totalling more than two hours.
The Argentine, who has been troubled recently by abdominal injuries, said his game was on the mend.
''I'm playing better, the first round is always tough,'' Nalbandian told reporters. ''I'm feeling much better than last week.'' Seven days ago, he lost 6-1, 6-2 to Italian Davide Sanguinetti in the opening round of the Toronto Masters.
Eighth seed Marcos Baghdatis, runner-up at the Australian Open and the newest member of the world's top 10, knocked out Thomas Johansson of Sweden 7-6, 7-6.
''It's been an amazing year for me. The only thing I need is to win a tournament,'' said the Cypriot.
Roger Federer and Rafael Nadal are the top seeds this week.