OBJECTIVE: Of patients who are prescribed metformin, 10-30% have evidence of reduced vitamin B12 absorption. B12-intrinsic factor complex uptake by ileal cell surface receptors is known to be a process dependent on calcium availability Metformin affects calcium-dependent membrane action. The objective of this study was to determine the magnitude and mechanism of the reduction in serum vitamin B12 after metformin administration. RESEARCH DESIGN AND METHODS: A comparative study design was employed using 2 groups (metformin and control). A total of 21 patients with type 2 diabetes received sulfonylurea therapy; 14 of these 21 patients were switched to metformin. Monthly serum total vitamin B12 measurements and holotranscobalamin (holoTCII) (B12-TCII) were performed. After 3 months of metformin therapy, oral calcium supplementation was administered. RESULTS: Serial serum vitamin B12 determinations revealed a similar decline in vitamin B12 and holoTCII. Oral calcium supplementation reversed the metformin-induced serum holoTCII depression. CONCLUSIONS: Patients receiving metformin have diminished B12 absorption and low serum total vitamin B12 and TCII-B12 levels because of a calcium-dependent ileal membrane antagonism, an effect reversed with supplemental calcium.