Serum gastrin has been reported to increase after therapy with some agents effective in the treatment of duodenal ulcer (DU). Misoprostol, a prostaglandin E1 analog, is effective in the treatment of DU, with healing rates similar to those achieved with vigorous antacid therapy or H2-receptor antagonists. Misoprostol reduces gastric acid secretion and also possesses cytoprotective properties. This multicenter study examined serum gastrin levels before and after treatment of DU patients with misoprostol. Sera for gastrin measurement were obtained from DU patients after an 8-hr fast, and 15 and 30 min after a standard mixed meal. DU patients were studied before and after two to four weeks of treatment with placebo or misoprostol: in one study, misoprostol 100 micrograms qid (without antacid) was compared with placebo; in the other study, misoprostol at 50- or 200-micrograms qid dosages (with limited antacid, Amphojel up to 54 meq/day) was compared with placebo. In addition, the serum gastrin values obtained in healthy subjects were compared with those from DU patients. Fasting and postprandial serum gastrin concentrations were essentially similar for DU patients and healthy subjects. There were no significant differences, either in fasting serum gastrin or in integrated gastrin responses, in DU patients after treatment with placebo or misoprostol at 100 micrograms (P = 0.32), 50 micrograms, or 200 micrograms doses (P = 0.85). It is concluded that misoprostol, when administered four times daily for two to four weeks at dosages required for the acceleration of DU healing, does not affect serum gastrin levels.