This study compared the effects of placebo with a carotenoid compound, crocetin, as well as an antioxidant, ascorbic acid, on physical fatigue in humans. In this double-blind, placebo-controlled, 3-way crossover study, 14 Japanese healthy volunteers (7 men and 7 women) were randomized to oral administration of crocetin (15 mg), ascorbic acid (3,000 mg), or placebo for 8 days. Subjects performed workload tests on a bicycle ergometer at fixed workloads for 120 minutes at 2 times (a total of 240 minutes) as a fatigue-inducing physical task. During the physical task, subjects performed nonworkload tests at maximum velocity (MV) of 10 seconds at 30 minutes (30-minute test) after the start of the physical task and at 30 minutes before the end of the task (210-minute test). The change in MV from the 30- to the 210-minute test was significantly higher in men who received crocetin compared with men who received placebo (P < .05). This effect of crocetin was specific to males. Administration of ascorbic acid did not change in MV from the 30-minute to the 210-minute test on males or females. These results suggest that daily administration of crocetin may attenuate physical fatigue in men.