The effect of H2-receptor antagonists on alcohol absorption appears to vary, depending on testing conditions and subject population. In this crossover study of cimetidine (400 mg b.i.d.) and ranitidine (150 mg b.i.d.), we evaluate alcohol pharmacokinetics in 10 subjects after ingestion of moderate doses (0.5 g/kg) of ethanol under four challenge conditions: (a) a single dose of placebo prior to alcohol ingestion in the morning, (b) a single dose of H2-antagonist prior to alcohol ingestion in the morning, (c) 14-day chronic dosing with H2-antagonist prior to alcohol ingestion in the evening, and (d) 28-day chronic dosing with H2-antagonist prior to alcohol ingestion in the morning. No significant increases were observed for alcohol in the area under the curve (AUC) or Cmax. Significant decreases in AUC (16 and 13%) were observed following administration of single- and multiple-dose cimetidine, and a significant decrease in Cmax (14%) was observed following a single dose of ranitidine--all given prior to alcohol ingestion in the morning. These results do not support any clinically meaningful effect of H2-antagonists on alcohol absorption following ingestion of a moderate dose of ethanol.