In a series of previous studies, we showed that misoprostol protects the gastric and duodenal mucosae against ulceration seen with the administration of both aspirin and the nonsteroidal antiinflammatory drug tolmetin. The purpose of this study was to confirm, in addition, that misoprostol protects the mucosae against aspirin-induced damage and, for the first time, to compare its cytoprotective properties with those of sucralfate. Thirty healthy volunteers were randomized into three equal groups receiving either misoprostol 200 micrograms, sucralfate 1 g, or placebo, co-administered with 650 mg of aspirin, four times a day for 7 days. All subjects had endoscopically normal mucosae on entry and were reendoscoped 2 h after a single final dose on day 7. The mucosae were graded on a 0-4 scale as follows: 0 = normal, 1 = single hemorrhage or erosion, 2 = 2-10 hemorrhages or erosions, 3 = 11-25 hemorrhages or erosions, 4 = more than 25 hemorrhages or erosions or an invasive ulcer of any size. Utilizing a previously established criterion of a score of 2 or less as a clinically significant degree of protection to the gastric mucosae, we found that the success rate for misoprostol was 100% (10/10), compared to 20% (2/10) for sucralfate and 0% (0/10) for placebo. Misoprostol was statistically significantly superior to both sucralfate (p = 0.0001) and placebo (p = 0.00001), with 95% confidence intervals on the difference in success rates between misoprostol and sucralfate and between misoprostol and placebo of (44%; 100%) and (61%; 100%), respectively. In the duodenum, nine of 10 subjects taking misoprostol showed no damage (0 grade), whereas this was seen in only five sucralfate and three placebo patients. Misoprostol was significantly superior to placebo (p = 0.020) and marginally superior to sucralfate (p = 0.141) with confidence intervals of (29%; 91%) and (-5%; 67%), respectively. Adverse experiences were minor and did not differ in the three groups.