Proton pump inhibitors (PPIs) and histamine‐2 receptor antagonists (H2RAs) may reduce the risk of oesophageal adenocarcinoma (OAC) in Barrett's oesophagus; however, current epidemiologic studies are inconclusive.

To evaluate the independent effects of PPIs and H2RAs on risk of OAC in patients with Barrett's oesophagus.

We conducted a nested case‐control study of male veterans diagnosed with Barrett's oesophagus. Cases with incident OAC were matched by incidence density sampling on birth year and Barrett's diagnosis date to controls with Barrett's oesophagus who did not develop OAC. We identified prescription medication usage 1 year prior to Barrett's oesophagus diagnosis to 3 months prior to the OAC diagnosis. Odds ratios (OR) and 95% CI were estimated using conditional logistic regression.

Compared with 798 controls, the 300 cases were less likely to use PPIs (90.0% vs 94.5%, P = 0.01) and H2RAs (19.7% vs 25.7%, P = 0.04). In the multivariable model including the use of statins, H2RAs, aspirin and nonsteroidal anti‐inflammatory drugs, PPI use was associated with 41% lower risk of OAC (OR 0.59, 95% CI 0.35‐0.99). While risk reduction of OAC was stronger for high‐dose PPIs (omeprazole daily dose >40 mg, adjusted OR 0.11, 95% 0.04‐0.36), we did not find a dose‐response relationship with PPI duration (P trend = 0.45). Likewise, H2RA use was independently associated with 30% lower risk of OAC (OR 0.70, 95% CI 0.50‐0.99).

Use of PPIs and H2RAs among patients with Barrett's oesophagus are associated with lower risk of OAC. Further clinical trials are needed to confirm this possible chemopreventive effect.