The effect on exercise performance and on the subjective perception of fatigue of the opioid receptor blocker naloxone, the nonselective beta-blocker timolol, and the combination of these two was studied in a double-blind randomized cycle ergometry test in healthy young men. Cumulative work at exhaustion was reduced by 25% after timolol (P less than 0.002) and by 34% after naloxone/timolol (P less than 0.02) but not after naloxone, compared with placebo. Naloxone alone had no influence on the subjective perception of fatigue (Borg scale rating), but significantly higher ratings were obtained by timolol and by naloxone/timolol. The present study does not support the hypothesis that opioid peptides are of importance for maximal exercise capacity and subjective perception of fatigue during short-term dynamic exercise in healthy young men.