Valencia - Fifth seed John Isner has crashed out of the Valencia Open in the first round to Spanish veteran Tommy Robredo 7-6 (7/3), 6-3 on Tuesday.
The American, who has only won two matches in four visits to Valencia, lost the opening set in a tie-break after neither man could make an impact on the other's serve.
And world number 21 Robredo got the all-important break in the penultimate game of the match before serving it out for a first win over Isner in four attempts.
Robredo will now face Chinese Taipei's Yen-Hsun Lu in round two.
Fourth seed Feliciano Lopez had an easier afternoon as he eased past Slovakian Norbert Gombos 6-4, 6-4 in little over an hour to set up a last-16 meeting with fellow Spaniard Pablo Carreno Busta.
Big-serving South African Kevin Anderson was also a winner in straight sets as he downed Germany's Philipp Kohlschreiber 6-3, 6-4.
Anderson is a potential quarter-final opponent for Andy Murray, who continues his quest to reach the World Tour Finals against Jurgen Melzer on Wednesday, and will face Slovakia's Martin Klizan in the second round.
France's Gilles Simon was another seed to fall as he was swept aside by Alexandr Dolgopolov 6-0, 6-3.
And Italy's Fabio Fognini enjoyed an unusually drama free day as he cruised past Spaniard Albert Ramos-Vinolas 6-4, 6-2.
The top two seeds David Ferrer and Thomas Berdych get their campaigns underway on Wednesday against Andreas Seppi and Pablo Andujar respectively.
Collated results from day two of the ATP Valencia Open on Tuesday (x denotes seeding):
Tommy Robredo (ESP) bt John Isner (USA x5) 7-6 (7/3), 6-3
Dusan Lajovic (SRB) bt Joao Sousa (POR) 6-3, 7-6 (10/8)
Feliciano Lopez (ESP x4) bt Norbert Gombos (SVK) 6-4, 6-4
Alexandr Dolgopolov (UKR) bt Gilles Simon (FRA x8) 6-0, 6-3
Jeremy Chardy (FRA) bt Malek Jaziri (TUN) 6-2, 6-1
Fernando Verdasco (ESP) bt Leonardo Mayer (ARG) 6-4, 3-6, 6-3
Kevin Anderson (RSA x7) bt Philipp Kohlschreiber (GER) 6-3, 6-4
Fabio Fognini (ITA) bt Albert Ramos-Vinolas (ESP) 6-4, 6-2