Salmon calcitonin stimulates both adenylate cyclase and guanylate cyclase systems in human kidney cortical cells but does not modify the cyclic nucleotide levels of medullary cells. In order to compare the effect of mammalian calcitonin and of calcitonin from the ultimobranchial body on cyclic nucleotides, the action of both salmon and human calcitonin was compared in intact kidney cells. The role of the regulatory unit in relation to the stimulation exerted by both calcitonins on the adenylate cyclase activity of kidney plasma membranes was also studied. Low concentrations of human calcitonin produced a significant increase of cyclic GMP accumulation in human kidney cortical cells. Higher hormone doses, active in stimulating the adenylate cyclase system, resulted in a progressive decline of the response. In kidney medullary cells human calcitonin was a more efficacious and potent stimulator of cyclic AMP than of cyclic GMP accumulation. Neither of the two calcitonins stimulated kidney cortical or medullary plasma membrane adenylate cyclase in the absence of guanylyl 5'-imidodiphosphate. However, in the presence of guanylyl 5'-imidodiphosphate, both calcitonins stimulated the cortical adenylate cyclase system. Under the same conditions, medullary adenylate cyclase activity was stimulated only by human calcitonin. These observations suggest that human calcitonin stimulates cyclic nucleotide accumulation in human kidney cortex and medulla, while salmon calcitonin is active only at the cortical level. This phenomenon could be explained on the basis of hormone-receptor binding.