Mild irritants have been shown to protect the rat gastric mucosa against noxious agents. This study was designed to test the protective potential of low-dose ethanol against acetylsalicylic acid (ASA) -induced gastric injury. Ten healthy volunteers who were nondrinkers and had normal baseline upper gastrointestinal endoscopy participated in a randomized double-blind crossover study. Thirty minutes after either vodka (37.5 ml) in tomato juice or tomato juice alone, each subject took 975 mg ASA and then underwent endoscopy 1 hr later. The degree of mucosal injury was scored, and blood was taken for ethanol and salicylate levels. There was a washout interval of seven days between the two treatments. Endoscopic scores were analyzed using the sign test. After a single dose of ASA, mucosal injury was confined to the fundus and antrum, while the duodenum was minimally affected. A significant reduction in antral damage was seen with ethanol pretreatment (P less than 0.05). The same trend was evident in the fundus but did not achieve statistical significance. Serum salicylate levels averaged 13.2 +/- 0.8 mg/100 ml and were not different between the two treatments. Ethanol concentration ranged from 1.1 to 6.2 mmol/liter following the vodka drink and was 0 after the placebo.