OBJECTIVE: This evidence-based review evaluates the therapeutic comparability of five proton pump inhibitors (PPIs): omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole for short-term treatment of uncomplicated gastroesophageal reflux disease (GERD). METHODS: A literature search identified 68 randomized clinical trials comparing the PPIs to each other, to placebo and/or to other anti-reflux treatments (histamine-2-receptor [H2]-blockers). Evidence tables were compiled for common outcomes and meta-analyses conducted. Efficacy was assessed on heartburn relief, esophageal healing, overall GERD symptom relief, and withdrawals due to lack of efficacy. Safety was analyzed using withdrawals due to adverse events, total adverse events, abdominal pain, diarrhea, nausea and headache. RESULTS: Meta-analyses found no differences between the PPIs in heartburn relief, overall GERD symptom relief, and withdrawals due to lack of efficacy. The analysis detected a statistically significant efficacy advantage of esomeprazole (20 and 40 mg/day) over omeprazole (20 mg/day) in acute erosive esophagitis healing rates. Broad and specific safety outcomes were comparable among the PPIs. CONCLUSION: In the evidence collected here, the five PPIs appear to be generally comparable for relief of GERD symptoms. For treatment of acute erosive esophagitis, both doses of esomeprazole were shown here to be more beneficial than omeprazole (20 mg/day). In terms of safety, the PPIs as a class have a remarkably low incidence of side effects with few differences between them. Further evaluation is needed to determine the safety of long-term use.