To determine whether the first-pass metabolism (FPM) of orally consumed alcohol varies with the time of day, 12 healthy male subjects were tested with both oral and intravenous alcohol (0.3 g/kg), in the morning and evening, always 1 hr after the same standard meal. The results revealed no significant differences in FPM (81.6±11.6 vs 92.8±10.6 mg/kg) or in any other index of alcohol absorption and metabolism. Eleven subjects were also tested in the evening after treatment with cimetidine, an H₂-antagonist that inhibits gastric alcohol dehydrogenase activityin vitro. Compared to baseline, cimetidine (1 g/day for eight days) significantly decreased FPM (from 100.1±8.0 to 52.6±11.4 mg/kg,P<0.01) and increased the systemic bioavailability of alcohol (from 66±3 to 82±4%,P<0.01), as well as peak blood alcohol concentrations (from 4.3±0.4 to 5.9±0.5 mM,P<0.05) and areas under the curve (from 5.1±0.5 to 7.0±0.5 mM/hr,P<0.01). The results indicate the absence of diurnal variation in FPM and suggest that patients given cimetidine should be warned of its possible interaction with alcohol regardless of the time of day.