The purpose of the present study was to examine the effect of a selective serotonin (5-HT) reuptake inhibitor (SSRI) on exercise performance during a 90 min time trial. Eight well trained male cyclists (VO2max 68.1 +/- 9.5 ml/kg/min) performed three 90 min time trials at 65% Wattmax. Blood samples were collected via an indwelling venous catheter for adrenocorticotropin hormone (ACTH), prolactin (PRL), cortisol, catecholamines, growth hormone (GH) and beta-endorphins. The evening before and the morning of the time trials, the subjects ingested a capsule containing either placebo (lactose) or 20 mg Fluoxetine-HCI (Prozac, Ely Lilly Belgium). A double blind, randomized, placebo controlled, cross-over design was performed. Performance was not influenced by the SSRI. As expected, all blood parameters increased significantly during exercise (p < 0.05). During the SSRI trial most parameters were slightly lower but only significantly for endorphins and PRL (p < 0.05). The results demonstrate that performance is not influenced by an SSRI, although some plasma hormones indicate a central effect of the drug. Surprisingly, the increases in PRL and endorphins were lower during the SSRI trial, meaning that the hormonal modulation during exercise might be regulated by the interaction between neurotransmitters rather than by serotonin alone.