BACKGROUND: Assimilation of vitamin B,2 from dietary sources requires gastric acid. By decreasing acid production, the proton pump inhibitors (PPIs) and histamine(2) (H-2)-blockers may reduce vitamin B-12 absorption. OBJECTIVE: To determine whether chronic acid suppression therapy is associated with the initiation of vitamin B-12 supplementation, we conducted a retrospective case-control study using a state-wide Medicaid population. METHODS: Case patients were identified as those who initiated vitamin B-12 supplementation during the study period. Four control patients were age- and gender-matched to each case. Patients (n = 109 844) with a paid claim between September 27, 1995, and September 27, 1997, were eligible for inclusion. Chronic acid suppression therapy was defined as treatment with H-2-blockers or PPIs for greater than or equal to 10 of the 12 months prior to the first vitamin B-12 injection. Comparisons were made between the case and control groups regarding exposure to chronic acid suppression therapy. RESULTS: One hundred twenty-five cases were matched to 500 controls. Twenty-three patients (18.4%) had been exposed to chronic acid suppression therapy compared with 55 (11.0%) of the control group (p = 0.025; OR 1.82; 95% Cl 1.08 to 3.09). CONCLUSIONS: Initiation of vitamin B-12 supplementation was associated with chronic gastric acid suppression therapy.