Hypercalcemia complicating malignancy is a frequent complication in adults, but little has been published about the pathogenesis or the true incidence of hypercalcemia in children with cancer. Hypercalcemia developing in childhood malignancies was studied retrospectively at St. Jude Children's Research Hospital to determine its incidence, the timing of its presentation, and its response to therapy. Over a 29-year period, 25 children (median age, 9.5 years) had been diagnosed and treated for hypercalcemia that occurred during the course of their malignancy. These 25 represented 0.4% of the total number of children treated for cancer at the institution during that period. Their malignancies comprised acute leukemias (11; 0.6%), rhabdomyosarcoma (4; 1.2%), malignant rhabdoid tumor (2), Hodgkin disease (1), non-Hodgkin lymphoma (1), hepatoblastoma (2), neuroblastoma (1), brain tumor (1), angiosarcoma (1), and a solid malignant tumor of undetermined type. Patients with acute lymphoblastic leukemia were more likely to present with hypercalcemia at the time of their initial diagnosis and to achieve resolution of this complication, whereas patients with solid tumors presented with hypercalcemia later in the course of their disease and had hypercalcemia that was more resistant to therapy. In contrast to adults with cancer, hypercalcemia of malignancy is extremely rare in children.