Ethanol causes mucosal injury to the stomach and which accompanied by back-diffusion of H⁺. Using several drugs known to modify the gastric acid secretion and to provide cytoprotection the effect of back-diffusion of H⁺ by ethanol was examined. Following 48 hours of starvation rats were anesthetized with urethane, and their stomachs were filled with 4 ml of 20% ethanol solution containing 1.8 mM HCI (7.2 µEq/4 ml) every 15 min. H⁺ content of the collected perfusates was determined by back-titration to pH 6.0. The presence of ethanol in the stomach for 1 hour caused a loss of luminal H⁺ at a rate of 4.8±0.4 µEq/15 min. Pretreatment of rats with atropine (2 mg/Kg, i.v.), pirenzepine(2 mg/Kg. i.v.), cimetidine (10mg/Kg i.v.), cromolyn sodium (20mg/Kg/hr, i.v.) or domperidone (1 mg/kg. i.v.) did not affect the ethanol-induced H⁺ back-diffusion. Similarly, no effect was seen in rats treated with prostaglandin E₂ (100 µgram/Kg i.v.) or indomethacin (5 mg/Kg, s.c). The addition of procaine (10^-5~10^-3 M) or propranolol (10^-9~10^-5 M) to the perfusate did not cause any changes in the ethanol-induced H⁺ back-diffusion. However, pretreatment of rats with acetazolamide (100 mg/Kg i.v.) or ethoxzolamide(50 mg/Kg/day, p.o. for 6 days), carbonic anhydrase inhibitors, markedly suppressed the ethanol-induced loss of luminal H⁺. Based on these results, it is suggested that ethanol-induced back-diffusion of H⁺ is mediated, at least in part, by the activity of carbonic anhydrase, and that cholinergic, histaminergic and dopaminergic mechanisms are not involved. Moreover, the implications of prostaglandins and membrane stability are not suggested.