Background & Aims: Rebound increased acid secretion has been observed at 2 weeks after discontinuing omeprazole treatment in Helicobacter pylori-negative, but not H. pylori-positive, subjects. It is unknown whether this is a prolonged phenomenon or whether a similar phenomenon appears later in H. pylori positives or is released by eradication therapy. The aims of this study were to answer these 3 questions. Methods: Twelve H. pylori-negative and 20 H. pylori-positive subjects were studied. Each had a basal, submaximal, and maximal pentagastrin-stimulated acid secretion study before, during, and at 7, 14, 28, 42, and 56 days after a 56-day course of omeprazole 40 mg/day. Ten of the H. pylori-positive subjects had their infection eradicated during the last week of treatment. Results: In the H. pylorinegative subjects, there was rebound secretion of submaximal (P < 0.003) and maximal (P < 0.003) acid output, which persisted until at least 56 days after discontinuing omeprazole. The H. pylori-uneradicated subjects had no rebound increased secretion other than in maximal acid output at 28 (P < 0.01) and at 42 days after treatment (P < 0.02). In those eradicated of H. pylori close to the end of omeprazole, there was rebound increased secretion of submaximal acid output (P < 0.04) lasting until 56 days and of maximal acid output (P < 0.01) lasting until 28 days after treatment. Conclusions: Rebound increased acid secretion following orneprazole is a prolonged phenomenon in H. pylorinegative subjects. There is little evidence of it in H. pylori-infected subjects, but eradicating the infection releases the phenomenon. The accentuated H. pylorirelated oxyntic gastritis induced by orneprazole is likely to protect against the rebound phenomenon.