Blood cells have been widely used to evaluate the status of the insulin receptor in man. The insulin receptor of human monocytes has been shown to mirror pathophysiologic states of insulin receptors in target tissues of animal models. Thus, comparison of the properties of the insulin receptor studied simultaneously in erythrocytes and monocytes is appropriate. We studied 19 normal subjects and 32 patients with diverse conditions such as acromegaly, insulinomas, insulin-dependent diabetes mellitus, corticosteroid administration, and the Type A and B forms of insulin resistance. We find that specific insulin binding at tracer concentrations significantly correlate (P < 0.001) for the two cell types obtained from these individuals. However, the total number of binding sites (Ro) and affinity of the receptor at the lowest insulin concentration (Ke) do not significantly correlate (P < 0.1). Monocytes from patients with the Type A and B forms of insulin resistance exhibit marked alterations in insulin binding and simultaneous studies in erythrocytes reflect these changes. The administration of 40 mg/day of prednisone for 3 days to normal subjects produced no significant change in insulin binding to either cell type. Insulin binding to both cell types from poorly controlled insulin-dependent diabetes mellitus patients was similarly normal or elevated. However, improved control decreased insulin binding in monocytes, but not in erythrocytes. We conclude that there is a general relationship between monocyte and erythrocyte insulin binding, but important differences exist in the way their insulin receptors are regulated. Insulin binding in erythrocytes is inversely and exponentially related to cell age. Unlike erythrocytes, monocytes represent a more uniform population of cells capable of the same receptor-mediated endocytotic functions as hepatocytes. Thus, the monocytemay provide a clearer reflection of the insulin receptor status in target tissues.