Humoral hypercalcemia of malignancy (HHM) results from the production of PTH-related protein (PTHrP) by human tumors. One previous study has reported the results of human (h) PTHrP(1-34) infusion into humans. In that report, hPTHrP(1-34) was found to be qualitatively similar to but 3- to 10-fold less potent than hPTH(1-34). Because hPTHrP(1-36) and not hPTH(1-34) is likely to be the actual amino-terminal secretory form of PTHrP, and because this previously reported lack of potency was unexpected, we repeated these studies using hPTHrP(1-36) and compared the results with those obtained with hPTH(1-34). Healthy subjects (n = 30) were infused over 6 h with either vehicle alone, hPTH(1-34) at a dose of 8 pmol/kg.h, or hPTHrP(1-36) at doses of 8 or 80 pmol/kg.h. Both hPTH(1-34) and hPTHrP(1-36) caused an increase in serum ionized calcium, a decrease in serum phosphorus, an increase in the fractional excretion of phosphorus, a decrease in the tubular maximum for phosphorus, an increase in nephrogenous cAMP excretion, and suppression of endogenous PTH(1-84). Unlike events observed in HHM, hPTHrP(1-36) induced an increase in plasma 1,25-dihydroxyvitamin D2. In addition, fractional excretion of calcium was reduced by both hPTH(1-34) and hPTHrP(1-36). In their actions on serum calcium, renal calcium and phosphorus handling, and nephrogenous cAMP excretion, hPTHrP(1-36) and hPTH(1-34) appeared equivalent in potency. These studies indicate that short-term infusion of hPTHrP(1-36) into humans reproduces most but not all of the features of HHM. In contrast to the reported findings with hPTHrP(1-34), we found the potency of hPTHrP(1-36) to be comparable with that of hPTH(1-34) in vivo in humans. In addition, unlike the situation in HHM, hPTHrP(1-36) produces an increment in plasma 1,25-dihydroxyvitamin D2. Finally, hPTHrP(1-36) has been shown for the first time to have anticalciuric effects in humans. This would suggest that, in addition to osteoclastic bone resorption, tubular reabsorbtion of calcium by hPTHrP may contribute to the hypercalcemia in patients with HHM.