OBJECTIVES: To compare the cost-effectiveness of esomeprazole versus pantoprazole and generic omeprazole from the perspective of the statutory health insurance using a decision model reflecting naturalistic treatment behaviour in GERD patients in Germany. METHODS: The model applies to patients with endoscopically verified GERD receiving PPI therapy and covers a period of 8 weeks. Therapies included were esomeprazole 20 and 40mg, omeprazole 20 and 40mg and pantoprazole 40mg. Real-life treatment patterns and resource utilization for acute and maintenance treatment were derived from 30 physician interviews, whereas healing rates after 4 and 8 weeks of treatment were derived from published literature. Resource utilization included visits, examinations and laboratory tests at primary care physicians and specialists, drug treatment of GERD, hospitalizations and working incapacity. RESULTS: Total costs per patient ranged between 137€ for esomeprazole and 202€ for pantoprazole with total healing rates after eight weeks between 85% (omeprazole) and 96% (esomeprazole). No hospitalizations were observed and the few sick leaves reported were shorter than 42 days, inducing no costs from the insurance perspective. Costs per patient healed varied between 145€ (esomeprazole) and 218€ (pantoprazole), with most of the treatments ranging closely around 200€. Due to the relatively small sample size, we tested the robustness of the results by conducting sensitivity analyses representing different degrees of standardization in input parameters. Cost-effectiveness did not differ much in either scenario; standardizing e.g. physician costs and treatment duration resulted in costs per patient healed between 163€ (esomeprazole) and 210€ (omeprazole). CONCLUSIONS: The results indicate that esomeprazole is a cost-effective treatment option for patients with endoscopically verified GERD treated over 8 weeks. Strongest competitor for esomeprazole is treatment with generic omeprazole. The current model will be extended to a 6 month period as soon as the data from a currently completed study will become available.