Misoprostol, a synthetic prostaglandin E₁ analog is being evaluated in the treatment of peptic ulcer. It has been reported to have both antisecretory and cytoprotective properties. In this placebo-controlled, double-blind study, pretreatment with 200-g doses of misoprostol was evaluated in the prevention of gastric injury caused by aspirin. Five oral doses of misoprostol or placebo were administered over 24 hr followed by a single oral 1296-mg dose of aspirin 30 min after the fifth dose of test agent. Two hours later the gastric mucosa was examined with a small-caliber fiberendoscope. Protection was defined as no more than 10 petechiae and no more than two hemorrhagic streaks in the gastric mucosa. Twenty of 30 (67%) subjects who received misoprostol was protected, whereas only one of 30 (3%) subjects receiving placebo was protected. The difference between the effects of misoprostol and placebo was highly significant (P<0.001). we="" concluded="" that="" five="">g doses of misoprostol given over 24 hr protects the gastric mucosa from the injurious effect of a single dose of aspirin.