Intravenous aminohydroxypropylidene bisphosphonate (APD) normalizes serum calcium in most hypercalcemic cancer patients, however the optimal therapeutic scheme has not been established. We compared in a randomized prospective trial the efficacy and the tolerance of APD given as a 3-day treatment of daily 2-h infusions of 0.5 mg/kg·d in 250 ml of saline (group A) with single 24-h infusions of 1.5 mg/kg (group B) or of 0.5 mg/kg in 1 liter of saline (group C). Thirty-three cancer patients remaining hypercalcemic after a 48-h rehydration period were included and monitored daily until normocalcemia or treatment failure was documented. Serum calcium became normal in all but 1 patient (in group C) but remained normal for only 1 or 2 days in 4 other patients (1 in A, 1 in B, 2 in C). The decline in total or ionized serum calcium was slightly less marked in group C than in the two other groups, but the differences were not significant. The fall of fasting urinary calcium excretion was however significantly less rapid in group C (p < 0.05 from day 1 to day 4). Serum concentrations of iPTH and 1,25-dihydroxyvitamin D [1,25-(OH)2D] increased significantly in the three groups. Serum magnesium concentrations fell slightly from 1.41 ± 0.05 to 1.28 ± 0.04 mEq/liter (p < 0.001) after rehydration but returned to normal after APD administration (day 5, 1.52 ± 0.04 mEq/liter, p < 0.001 versus day 0). On the other hand, APD induced a fall in serum phosphate levels, from 2.9 ± 0.1 to 2.3 ± 0.1 mg/dl on day 4 (p < 0.001), without any significant change in TmP/GFR. Treatment was very well tolerated; we only observed 3 cases of drug-induced fever, 1 in each group. Based on this and other dose-response trials, we recommend a total dosage of 1.0 to 1.5 mg of APD/kg body weight for the therapy of tumor-associated hypercalcemia; this treatment can be safely and efficiently given as a single 24 h infusion or as daily 2 h infusions for 3 days.