The suppressive effects of cimetidine on acid, pepsin, and intrinsic factor secretion have been well documented; however, the effect of cimetidine on cobalamin absorption has not been assessed. The absorption of both unbound [57Co]cyanocobalamin and protein-bound [57Co]cyanocobalamin was evaluated in 12 patients with duodenal ulcer disease during and after discontinuation of cimetidine therapy. Cimetidine administration did not lead to malabsorption of unbound cobalamin but caused malabsorption of protein-bound cobalamin (0.22 +/- 0.08%, [mean +/- 1 SEM] versus 2.3 +/- 0.10% in control subjects, P less than 0.01). This malabsorption was reversible upon discontinuation of cimetidine. Patients on cimetidine therapy malabsorb protein-bound cobalamin and, during long-term treatment, are at risk for developing cobalamin deficiency. This malabsorption was reversible upon discontinuation of cimetidine. Patients on cimetidine therapy malabsorb protein-bound cobalamin and, during long-term treatment, are at risk for developing cobalamin deficiency. This malabsorption of protein-bound cobalamin is not detectable by the usual tests of cobalamin absorption which employ unbound cobalamin.