The present studies examined renal calcium (Ca) clearance in an animal model of malignancy-associated humoral hypercalcemia (MAHH) (a human squamous cell lung carcinoma carried in athymic mice). Three groups of animals--controls, normocalcemic tumor-bearing animals and hypercalcemic tumor-bearing animals--were studied in the basal state and during Ca infusion. Baseline Ca clearance was slightly but significantly elevated in the tumor-bearing hypercalcemic animals compared with the other two groups of animals. This clearance value was, however, inappropriately low for the serum Ca value. In the control and in the normocalcemic tumor-bearing animals, Ca clearance increased markedly during Ca infusion. This increase in renal Ca clearance was markedly blunted in the hypercalcemic animals compared with both the controls and the normocalcemic tumor-bearing animals. We conclude that increased renal Ca resorption contributes significantly to the pathogenesis of hypercalcemia of malignancy.