The protective effect of misoprostol against naproxen-induced gastric mucosal damage was the subject of a double-blind, randomized, parallel-group study. Thirty-two healthy subjects were treated with naproxen 500 mg twice daily and either misoprostol 200 micrograms or matching placebo twice daily for seven days. Gastroscopy was performed before and after the treatment period and the mucosa was assessed for erosive and petechial lesions according to a predetermined scoring scheme. Of 25 evaluable subjects, 12 were treated with misoprostol and 13 were treated with placebo. The mean overall endoscopic score was 1.24 +/- 0.09 with placebo and 0.26 +/- 0.07 with misoprostol. The difference, 0.98, was highly significant (p less than 0.001), with 95 percent confidence limits of 0.74 to 1.22. All subjects in the placebo group had higher mean scores than any in the misoprostol group. The scores for erosive and bleeding lesions in the antrum and corpus/fundus of the stomach were all reduced by administration of misoprostol. In conclusion, the results clearly demonstrate that misoprostol protects the gastric mucosa of humans against naproxen-induced damage.