OBJECTIVES: Patients with Gastro-Oesophageal Reflux Disease (GORD) in primary care usually receive empirical treatment based on symptoms, without referral for endoscopy. Esomeprazole is a new proton pump inhibitor, which has been shown to be superior to omeprazole in the healing of reflux oesophagitis. The objective of this analysis was to compare the cost-effectiveness of acute treatment for up to eight weeks with esomeprazole, 40 mg, od, or omeprazole, 20 mg, od, in patients with non-endoscoped GORD. METHODS: Based on results from clinical studies and from a UK physician survey of patient management in clinical practice, a simple decision analysis model was designed to compare the cost-effectiveness of the two treatment strategies. Time with GORD, defined as weeks with endoscopic lesions or weeks with GORD symptoms, was used as the measure of effectiveness. UK direct medical costs were used. Results were calculated from a National Health Service perspective. RESULTS: The esomeprazole strategy was dominant over the omeprazole strategy. Time with GORD was 3.3 weeks per patient in the esomeprazole strategy and 3.6 weeks in the omeprazole strategy. The esomeprazole strategy incurred lower direct medical costs than the omeprazole strategy. A sensitivity analysis showed that the results are sensitive to a change in drug costs for esomeprazole or omeprazole. However, when costs associated with a treatment failure after eight weeks are considered, the results indicate that the esomeprazole strategy is cost-saving even when drug costs for omeprazole, 20 mg, are reduced by more than one third. CONCLUSIONS: Esomeprazole is cost-effective compared with omeprazole for the acute treatment of patients with non-endoscoped GORD.