Viktor Troicki threw away a one-set lead to bow out at the hands of Spain's Daniel Gimeno-Traver at the Nastase Tiriac Trophy in Bucharest.
The Serb has failed to get past the round of 32 in a competition since February's run to the quarter-finals in Acapulco and that poor form continued with an upset against the world number 68.
Troicki saved just three of 10 break-points in the two-hour contest as he fell 7-5 3-6 1-6 - suffering a first defeat in four attempts against the Spaniard.
Gimeno-Traver will face Denis Istomin next while Mikhail Youzhny did things the hard way in his 1-6 6-4 6-3 victory against Marius Copil.
The experienced Russian trailed after a shocking first set, in which the wildcard served four aces, but recovered to progress in just over 90 minutes.
Sergiy Stakhovsky and Borna Coric met for the second this time this year, with the result going the opposite way to their clash at the Zagreb Indoors two months ago.
The Croatian world number 55 this time came through a close-fought encounter 6-2 6-7 (4-7) 7-6 (7-2).
Coric, 18, faces veteran countryman Ivo Karlovic in the next round, with the 36-year-old third seed handed a first-round bye.
World number 603 Florian Mayer was initially on course to shock Malek Jaziri, having moved ahead early before succumbing to a 4-6 6-4 7-5 defeat.
Mayer was making only his second appearance of 2015 but ran out of steam as the Tunisian claimed victory on their first career meeting.