Twelve healthy subjects were given aspirin (975 mg four times a day) for four days. On days three and four, each dose of aspirin was preceded by a synthetic protaglandin E1 analog (misoprostol, Searle) either 25 micrograms, 50 micrograms, or placebo in a double-blind balanced full crossover design. Bleeding, gastric secretion of acid and chloride, and accumulation of gastric luminal DNA and calcium as indices of cell shedding and mucus secretion were measured by three daily morning gastric washouts, corrected for gastric emptying. Both bleeding and gastric secretion were greater on day 4 with aspirin and placebo than on day 0. With 50 micrograms misoprostol, and to a lesser extent with 25 micrograms, bleeding and gastric secretion were reduced on day 4 compared to day 4 with placebo or aspirin only days. The reduction in gastric bleeding with the 50-microgram dosage of misoprostol was directly related to the reduction in acid secretion. The ratios of changes in acid and chloride outputs did not indicate any increase in bicarbonate secretion. No changes in the recoveries of calcium or DNA were seen.