Both the calcium ion and calmodulin have been proposed to play a role in producing the intracellular effects of insulin. Abnormalities in calmodulin levels have previously been reported in tissues from diabetic animals. Thus, using a sensitive and specific radioimmunoassay, we measured calmodulin levels in red cells and polymorphonuclear leukocytes from humans with diabetes mellitus. Diabetic patients have significantly lower white cell calmodulin levels than age-matched controls. There were no significant differences in red cell calmodulin levels in diabetics compared with controls. Red cell calmodulin levels in normal subjects were decreased with advancing age. We conclude that the alteration in calmodulin levels in leukocytes from diabetics may be associated with the decreased neutrophil function that has been observed in diabetics.