Top seed John Isner eased through his Delray Beach opener, but second and third seeds Marin Cilic and Viktor Troicki exited on Tuesday after losing their matches in three sets.
World number 11 Isner needed a 32-point second set tie-break to oust American wild card Jesse Levine 6-4, 7-6 (17/15) at the $442,500 Delray Beach International Championships.
Jurgen Melzer, who won the Memphis Open title last week, was also eliminated in his opening match Tuesday.
It was the first Delray Beach match win for Isner who lost in the first round of the hardcourt tournament to Teymuraz Gabashvili in his only other appearance last year.
Isner, who is chasing his fourth career ATP Tour title, saved five set points and boosted his tie-break record this season to an impressive 9-1.
Cilic lost to Finland's Jarkko Nieminen 6-3, 3-6, 6-2. He was competing in his first event of the season after being sidelined with a left knee injury for two months.
Troicki lost his serve seven times en route to a 6-4, 4-6, 6-4 defeat at the hands of Belgian Steve Darcis.
American qualifier Tim Smyczek ousted Melzer 6-4, 2-6, 7-5 as he broke the Austrian's serve five times.
It marked the first win in almost a year for Smyczek, who is ranked 287th in the world.
Melzer is fresh off a victory in the final of the Memphis Open where he beat rising Canadian star Milos Raonic on Sunday.
In other matches on Tuesday, fifth seed Philipp Kohlschreiber hammered 13 aces to get past Olivier Rochus of Belgium 6-1, 6-4 in the third match of 2012 between the two.
Rochus won their semi-final at the Heineken Open in Auckland before Kohlschreiber won their Open Sud de France match at Montpellier earlier this month.
Latvian Ernests Gulbis, two-time champion Xavier Malisse, and South African Kevin Anderson also won their opening matches on Tuesday.