OBJECTIVES: This study evaluated cost, percentage of successfully treated patients and cost per successfully treated patient comparing two branded Proton Pump Inhibitors (PPIs) often prescribed in the UK, lansoprazole (oro-dispersible tablets) and esomeprazole (tablets), for the acute management of uninvestigated dyspepsia. METHODS: A decision analytic model was used to simulate expected costs and outcomes in patients with uninvestigated dyspepsia indicated for treatment with a PPI. The primary outcome measure was the percentage of patients cured within eight weeks, derived from studies directly comparing the efficacy of the two agents in this patient population. The analysis considered use of PPI drugs, general practitioner visits, subsequent specialist consultations and endoscopy. Costs were estimated from the perspective of the UK National Health Service. Stochastic methods were used to determine confidence intervals. RESULTS: The expected proportion of patients healed after 8 weeks was 88.9% (95% CI 87.7%-90.1%) with lansoprazole and 92.4% (91.4-93.3%) with esomeprazole. The expected cost of treatment per patient with lansoprazole was £94.05 (£85.17 – £104.58) compared with £118.94 (£110.28 – £128.83) with esomeprazole. The incremental cost-effectiveness of esomeprazole compared to lansoprazole was £711.77 (£465.41 – £1,344.52) per additional patient achieving healing at eight weeks. Sensitivity analysis exploring cost-effectiveness over twelve weeks found a cost-effectiveness of £2,213 (£1,487 – £4,087) per additional patient achieving healing. Esomeprazole was significantly more expensive than lansoprazole (26% more at 8 weeks; 37% more at 12 weeks; p<0.05 in both comparisons) and delivered a small but diminishing therapeutic advantage (3.9% at 8 weeks; 1.9% at 12 weeks). CONCLUSION: For patients presenting with uncomplicated reflux symptoms, treatment with esomeprazole was significantly more expensive than lansoprazole and its therapeutic advantage was small.