Two IgGIK monoclonal antibodies to human transcobalamin I1 (TC 11) were generated. These antibodies, 16.1 and 16.6, did not cross-react with the other two types of human cobalamin-binding proteins, intrinsic factor and R binder (TC I). Both antibodies cross-reacted with orangutan and simiang TC I1 but not with TC 11 from cynomolgus and howler monkeys, who are less closely related to humans. This finding suggests close structural similarity of human to ape TC 11. The antibodies also did not react with TC I1 of lower mammals which included the horse, dog, guinea pig, and mouse; in particular, reaction did not occur with rabbit TC 11, which has been considered structurally close to human TC 11. Neither of the two antibodies was directed at the cobalamin-binding site of TC 11. However, antibody 16.6 hindered TC I1 binding to cell receptor. This reactivity with the receptor-binding site should prove particularly useful in studies of that region of the TC I1 molecule. o