Summary Background Data suggest that esomeprazole decreases gastric secretion. Aims To assess the effect of a single i.v. esomeprazole dose on gastric secretion volume 3 h after drug administration, as a primary endpoint, and to evaluate, as secondary endpoints, the reduction 1 and 5 h after dosing; time when the gastric pH was <2.5 and esomeprazole’s safety. Methods In all, 23 healthy Helicobacter pylori ‐negative volunteers (10 men, 13 women, mean age 28.2 ± 6) participated in this single‐centre, randomized, double‐blind, placebo‐controlled, 2‐way, single‐dose cross‐over study. In different sessions, volunteers received i.v. either esomeprazole 40 mg or placebo. An inserted double‐lumen nasogastric tube perfused and aspirated gastric liquid. Mechanical fractioned aspiration measured secretion volume; aliquot spectrophotometry assessed gastric secretion volume lost to the duodenum. Results Three hours post‐i.v. esomeprazole, average gastric secretion decreased by 77.6% (vs. baseline) compared to placebo. Values 1 and 5 h after dosing were 73.5% and 74.5%. Five hours after esomeprazole, the gastric pH was <2.5 3.9% of the time and 73.3% after placebo ( P < 0.002). Esomeprazole was well‐tolerated. No serious adverse events occurred. Conclusions Intravenous esomeprazole decreases gastric secretions. The potential clinical impact in averting bronchoaspiration during anaesthesia induction and in intensive care patients should be investigated in further studies.