Chronic use of cimetidine and alcohol are commonly associated, but studies on their interactions are the subject of controversy. To investigate this question, a small ethanol dose (0.15 g/kg body wt) was randomly administered on 2 consecutive days either orally or intravenously to 6 normal volunteers, before and after 1 wk of oral administration of 400 mg of cimetidine twice daily. Although cimetidine did not change the areas under the curve of blood ethanol concentrations after intravenous administration, those after oral alcohol intake were twice as large with cimetidine than without. Similar effects were reproduced in rats after intravenous administration of cimetidine (50 mg/kg body wt). In vitro, cimetidine was a noncompetitive inhibitor of gastric alcohol dehydrogenase activity at concentrations as low as 0.01 mM, 100-fold lower than those needed to inhibit the hepatic dehydrogenase. These results indicate that gastric alcohol dehydrogenase activity governs, in part, the systemic bioavailability of ethanol. Consequently, systemic effects of alcohol may be exacerbated in patients receiving cimetidine.