The syndrome of humoral hypercalcemia of malignancy (HHM) is thought to be mainly a result of the production of parathyroid hormone-related protein (PTHRP) by malignant tumors. Serum 1,25-dihydroxyvitamin D (1,25-DHD) concentrations are generally low in such patients, which contrasts with the findings in animal studies. A patient is reported with HHM from a clear cell ovarian carcinoma and elevated serum immunoreactive PTHRP (about five times the upper limit of normal) in whom serum 1,25-DHD concentrations were abnormally high (200 pmol/l) and associated with increased intestinal calcium absorption. Treatment with two different nitrogen-containing bisphosphonates (pamidronate and [3-dimethyl-amino-1-hydroxypropylidene]-1,1-bisphosphonate) did not normalize serum and urinary calcium despite effective inhibition of bone resorption. These observations suggested an additional intestinal contribution to the maintenance of hypercalcemia. Tumor removal was followed by decreases in serum immunoreactive PTHRP and 1,25-DHD concentrations to their respective normal ranges and normocalcemia. Separating HHM into Types I and II, according to the prevailing serum 1,25-DHD concentrations, can provide a basis for a better understanding of the pathogenesis of hypercalcemia, and it also may have practical use in the successful management of these patients.