BACKGROUND & AIMS: The incidence of Barrett's esophagus and esophageal adenocarcinoma has increased despite surveillance of patients with Barrett's esophagus. Limited data indicate that nonsteroidal anti-inflammatory drug (NSAID) and statin use reduce the risk for esophageal adenocarcinoma. We investigated whether NSAID or statin use reduces the risk of neoplastic progression from Barrett's esophagus. METHODS: We performed a prospective study of 570 patients with Barrett's esophagus at 3 academic and 12 regional Dutch hospitals. Information on medication use was collected in patient interviews at each surveillance visit and cross-checked with pharmacy records. Patients completed a questionnaire about use of over-the-counter medication. Incident cases of high-grade dysplasia and adenocarcinoma were identified during the follow-up period. RESULTS: During a median follow-up period of 4.5 years, 38 patients (7%) developed high-grade dysplasia or adenocarcinoma. After Barrett's esophagus had been diagnosed, 318 patients (56%) used NSAIDs for a median duration of 2 months, 161 (28%) used aspirin for a median duration of 5 years, 209 (37%) used statins for a median duration of 5 years, and 107 (19%) used NSAIDs and statins. NSAID and statin use were each associated with a reduced risk of neoplastic progression (hazard ratio [HR], 0.47; P = .030 and HR, 0.46; P = .048, respectively). Use of a combination of NSAIDs and statins increased the protective effect (HR, 0.22; P = .028). CONCLUSIONS: NSAID and statin use reduce the risk of neoplastic progression in patients with Barrett's esophagus. Use of a combination of NSAIDs and statins appears to have an additive protective effect.