The effect of acute administration of indomethacin over 24 hours on basal and histamine stimulated gastric acid secretion was evaluated in seven normal male volunteers. Augmented histamine tests (0.015 mg/kg/h) infused with the antihistamine diphenhydramine hydrochloride (25 mg/h) were performed before and after pretreatment with indomethacin or matching placebo capsules. The dose of indomethacin was 75 mg (sustained release capsules) taken 12 and 24 hours before and 50 mg taken one hour before a two hour histamine infusion test. Indomethacin enhanced basal gastric secretion from 3.5 +/- 0.5 to 6.4 +/- 0.6 mmol/h (p less than 0.01) and histamine stimulated secretion from 48 +/- 6 to 62 +/- 5 mmol/2 h (p less than 0.05). Indomethacin significantly inhibited systemic prostaglandin biosynthesis as measured by urinary excretion (87 +/- 12 vs 41 +/- 6 ng PGE/g creatinine/h) and the drug increased platelet aggregation time two, five, and six fold, respectively, induced by ADP, collagen, and adrenaline. The data indicate that therapeutic doses of indomethacin augmented basal and secretagogue stimulated gastric acid secretion in control subjects. The enhancement of gastric acid secretion by indomethacin may be because of reduced levels of endogenous prostaglandins. Diminished prostaglandin biosynthesis may play a role in indomethacin induced gastric mucosal damage observed in patients receiving the drug.