Omeprazole, a potent and long-acting inhibitor of gastric acid secretion, is known to increase both serum gastrin and pepsinogen A and C levels in unoperated subjects. It has been suggested that the rise in serum pepsinogens is mediated by the omeprazole-induced increase in serum gastrin. This study was undertaken to determine the role of gastrin in hyper-pepsinogenemia induced by antisecretory therapy. We have studied the effect of a 5-day course of 40 mg of omeprazole daily on fasting serum gastrin and pepsinogen A and C levels in 14 patients with an antrectomy and a Billroth I anastomosis (n = 8) or a Billroth II anastomosis (n = 6). In antrectomized patients omeprazole failed to induce any increase in basal serum gastrin. On the other hand, omeprazole increased significantly serum pepsinogen A levels in both Billroth I and II patients, while the rise in serum pepsinogen C level was significant in Billroth I, but just failed to reach statistical significance in Billroth II patients. We conclude that the stimulation of serum pepsinogens A and C by a short-term treatment with omeprazole is not mediated by increases in serum gastrin. This study further shows that omeprazole stimulates gastrin release only from the antrum and not from extra-antral sources.