Although nocturnal acid secretion has been emphasized in the pathophysiology and treatment of duodenal ulcer, its importance in gastric ulcer disease has been questioned. To explore this area, this multicenter U.S. trial compared the effect of a once-daily nighttime dose of H2-receptor antagonist with placebo on the healing of gastric ulcer and relief of associated symptoms. One hundred fifty-seven patients with endoscopically verified benign gastric ulcers were randomized in a double-blind fashion to either famotidine (40 mg at bedtime) or placebo. Antacid tablets were allowed as needed. The healing rates for famotidine were 45%, 66%, and 78% at weeks 4, 6, and 8, respectively. In comparison, placebo healing rates were 39%, 44%, and 64%. These differences were statistically significant in favor of famotidine at weeks 6 (p less than or equal to 0.01) and 8 (p less than or equal to 0.05), as well as in a life-table analysis (p less than or equal to 0.05). Nocturnal famotidine was also significantly better than placebo with respect to time to complete relief of pain and to the percentage of patients with complete relief of pain. No concomitant factor (including ulcer size, ulcer location, smoking history, or regular alcohol use) affected healing rates in this study. Famotidine was well-tolerated and no serious clinical or laboratory adverse effects were judged to be related to this dosing regimen of famotidine. In conclusion, suppression of nocturnal acid secretion with famotidine (40 mg at bedtime) was more effective than placebo in promoting the healing of acute benign gastric ulcer and its associated symptoms. The results of this study suggest that suppression of nocturnal acid secretion alone is as effective as "around the clock" acid suppression in the healing of benign gastric ulcer.