Misoprostol (SC-29333), a synthetic prostaglandin E₁ methyl ester analog, was given simultaneously with acetylsalicylic acid in a double-blind, placebo-controlled randomized prospective study of 32 healthy human male subjects. Fecal blood loss was measured for eight days using the⁵¹Cr-labeled red blood cell technique. Aspirin (650 mg qid) and misoprostol (25 g qid) or placebo were given during days 3, 4, and 5. There was a significant (P<0.05) increase="" in="" median="" blood="" loss="" (modified="" friedman="" test)="" from="" 0.81="" to="" 6.05="" ml/day="" in="" the="" aspirin="" with="" placebo="" group="">N=16). Median blood loss was increased (from 0.75 to 3.75 ml/day) in the aspirin with misoprostol group (N=16), but this was significantly less (Mann-Whitney U test,P<0.01) than="" the="" placebo="" group.="" mean="" serum="" salicylate="" concentrations="" in="" the="" placebo="" and="" misoprostol="" groups="" were="" similar="" (7.8="" and="" 6.8="">g/ml, respectively). There were no significant changes in laboratory values in any of the subjects studied, nor were any major side-effects encountered. This study demonstrates that oral misoprostol reduces aspirin-induced gastrointestinal bleeding even when administered simultaneously and at a dose level below its threshold for significant acid inhibition. This indicates a potential role for misoprostol in the prevention of gastric mucosal damage in selected patients.