To identify the optimal pharmacodynamic dosing regimen for esomeprazole administered intravenously (i.v.) and to compare acid suppression with various esomeprazole i.v. and omeprazole i.v. dosing regimens. A total of 90 healthy Helicobacter pylori-negative subjects participated in three randomized, crossover studies of esomeprazole i.v. Comparative acid output study: an open-label study that compared single 40 mg i.v. doses (administered over 30 min) of esomeprazole and omeprazole. Dose-ranging study: an open-label study that compared acid control with five different doses of esomeprazole i.v., administered over 24 h. Comparative pH study: a double-blind study that compared esomeprazole i.v. and omeprazole at doses of 80 mg (over 30 min) + 8 mg/h (for 23.5 h). In the comparative acid output study, estimated mean pentagastrin-stimulated acid output was reduced from 33.9 mmol/h at baseline to 5.4 mmol/h at 4 - 5.5 h with esomeprazole vs. 9.5 mmol/h with omeprazole (p < 0.001). In the dose-ranging study, the 80 + 8 mg/h regimen provided a greater mean time with pH > 6 (12.6 h) than the lower doses (11.0 and 10.7 h for 40 + 8 mg/h and 80 + 4 mg/h, respectively) and significantly more time with pH > 4 (21.5 vs. 19.7 and 19.2 h, respectively; p < 0.05). In the comparative pH study, the mean number of h with pH > 4 was similar between esomeprazole (21.4 h) and omeprazole (21.1 h). Esomeprazole was superior to omeprazole in reducing stimulated acid secretion. Control of intragastric pH was similar for esomeprazole and omeprazole at a dose of 80 + 8 mg/h. An esomeprazole i.v. dosage regimen of 80 + 8 mg/h appeared to be optimal for acid suppression in healthy subjects under study.