The increase in gastrin caused by the gastric proton pump inhibitor, omeprazole, is presumably related to inhibition of gastric acid secretion (GAS). We investigated omeprazole's effect on gastrin release by studying two doses of omeprazole which produced marked acid suppression. Six gastric fistula dogs received omeprazole, 3 mumole/kg, daily for 20 days and, after a rest interval of 2 months, omeprazole, 10 mumole/kg again for 20 days. Both doses of omeprazole increased gastrin levels and produced a decrease in GAS which was still significant (P less than 0.05) 3 days postfinal dose. The increase in the integrated gastrin response by omeprazole, 10 mumole, was greater than by omeprazole, 3 mumole. Omeprazole, 10 mumole, also reduced GAS and gastric acidity, and increased gastric pH more consistently than omeprazole, 3 mumole. The magnitude of the gastrin response corresponded with the degree of acid inhibition and pH increase. Therefore, the data support the hypothesis that the hypergastrinemia caused by omeprazole is dependent on gastric pH and GAS suppression.