Seven healthy subjects exercised to exhaustion on a bicycle ergometer at a power output corresponding to 70% of maximum oxygen uptake after administration of either a placebo or 20 mg of paroxetine, a serotonin re-uptake inhibitor. Exercise time after paroxetine (median 94 min; range 84-127 min) was less (P < 0.05) than after placebo (median 116 min; range 86-133 min). The metabolic and cardiorespiratory responses to exercise were the same in both trials. This result supports the suggestion that there is a central component to fatigue which is mediated by the activity of serotoninergic neurones.