Humoral hypercalcemia of malignancy is a paraneoplastic syndrome believed to be due to production by the tumor of substances that stimulate osteoclastic bone resorption primarily. The human renal cell carcinoma cell line RC-8, grown in nude mice, was investigated for factors involved in renal cancer-induced hypercalcemia. At a tumor load of 200 to 400 mm.3 the mice developed hypercalcemia and hypophosphatemia associated with a rise in serum 1,25-dihydroxyvitamin D concentration and cachexia. The tumor released 1) significant amounts of human interleukin-6 (IL-6) and 2) parathyroid hormone-related peptide (PTHrP) into the circulation. Cancer cells further expressed mRNA for both human IL-6 and PTHrP. No secretion of human tumor necrosis factor-alpha or interleukin-1 beta could be demonstrated in the circulation of the host. Antibodies to IL-6 caused a significant (p = 0.043) inhibition of tumor growth and decreased serum calcium concentrations compared with control animals. Our data suggest that IL-6 is involved, either directly or indirectly, in the development of hypercalcemia in renal cell carcinoma.