Quantitative bone histology was studied in 23 patients with malignant hypercalcemia (MH) due to carcinoma (16) or immunoproliferative disease (7). Plasma calcium was 3.37 ± 0.47 (mean ± SD) mmol/liter. Bone resorbing surface (RS) was measured using a sensitive histochemical stain to identify osteo-clasts. In the MH patients with carcinoma, the RS was 3.1 ± 2.6% compared to 1.0 ± 0.3% in controls (P < 0.02). In the myeloma patients it was 2.3 ± 1.7%, and in normocalcemic patients with malignant disease 0.8 ± 1.1%. RS did not correlate with serum PTH, and several high RS values were associated with undetectable PTH. RS correlated with forming surface (FS) in MH patients (r = 0.44, P < 0.05) and controls (r = 0.68, P < 0.005), but there was a greater RS relative to FS in MH patients than in controls (P < 0.005). “Excess” RS in the MH patients was calculated by subtracting the RS accounted for by the measured FS, using the relationship defined by the controls. Bone loss, as reflected in urinary calcium excretion, correlated weakly with excess RS (r = 0.44, P < 0.05) but was high even when excess RS was zero. Thus, the histological findings do not account for the bone loss, and additional resorption around bone metastases is likely; the results of this study are consistent with a humoral substance produced by the malignant tissue causing generalized bone resorption in addition to bone dissolution around metastases.