Multiple myeloma frequently leads to complications, such as osteolytic lesions, hypercalcemia, and pathological fractures. Increased bone resorption in myeloma is due to osteoclast activation. The nature of the osteoclast activator(s) remains unclear. We describe a case of multiple myeloma with marked hypercalcemia and skeletal complications that progressed rapidly despite chemotherapy. The patient had marked hypercalcemia at diagnosis (4.5 mmol/l), and elevated parathyroid hormone-related protein (PTHrP) levels were found in plasma. Analysis of the bone marrow trephine biopsy showed PTHrP gene transcription and protein in myeloma cells. These results provide strong evidence for the production of significant amounts of PTHrP by human myeloma cells. PTHrP has been measured as elevated in the plasma of patients with myeloma and might be an important contributor to the skeletal complications in this disease.