OBJECTIVE: To determine whether the four histamine-2 receptor antagonists currently available for the treatment of acid-peptic disorders in the United States alter serum ethanol levels after moderate alcohol consumption. DESIGN: Prospective, randomized crossover design comparing the effects of histamine-2 receptor antagonists and no treatment on serum ethanol levels. Each participant served as his own control. PARTICIPANTS: Twenty-five healthy nonalcoholic men (21 to 35 years old); two participants were withdrawn before starting the study. SETTING: University medical center. INTERVENTION: Cimetidine (400 mg twice daily), famotidine (20 mg twice daily), nizatidine (150 mg twice daily), ranitidine (150 mg twice daily), and no treatment for 7 days. After the last dose of medication, participants ate a standard meal; 1 hour later they drank ethanol (0.3 g/kg body weight in 500 mL of orange juice) over 8 minutes. MEASUREMENTS: Simultaneous measurements of breath and serum (headspace gas chromatography) ethanol were made before and 10, 20, 30, 45, 60, 90, 120, 150, and 180 minutes after ingestion of ethanol. RESULTS: Peak ethanol levels did not differ (mmol/L; mean +/- SE) after cimetidine (3.0 +/- 0.3), famotidine (2.9 +/- 0.3), nizatidine (2.9 +/- 0.3), ranitidine (3.1 +/- 0.4), and no treatment (2.9 +/- 0.4). Similarly, there was no difference in the area under the curve (mmol/L.h; mean +/- SE) after cimetidine (4.3 +/- 0.5), famotidine (3.8 +/- 0.4), nizatidine (4.2 +/- 0.5), ranitidine (3.9 +/- 0.4), and no treatment (4.0 +/- 0.5). CONCLUSIONS: In healthy nonalcoholic men, the histamine-2 receptor antagonists currently available in the United States do not alter serum ethanol levels following moderate alcohol consumption after an evening meal.