Hypercalcemia in childhood acute lymphoblastic leukemia (ALL) is rare and occasionally associated with parathyroid hormone‐related protein (PTHrP). However, the pathogenesis of PTHrP‐independent hypercalcemia remains unclear. We report two children with precursor B ALL who had marked hypercalcemia (15.8 and 16.6 mg/dl, respectively) and disseminated osteolysis. Serum tumor necrosis factor‐α (TNF‐α) and IL‐6 were markedly elevated, whereas 1,25(OH)₂ vitamin D₃, intact PTH and PTHrP were decreased or undetected. Analysis of urinary deoxypyridinoline (DPY) or bone biopsy of the osteolytic lesion showed an increased bone resorption, and administration of bisphosphonate improved the hypercalcemia. Patients had ALL with immunophenotype positive for CD10, CD34, and HLA‐DR but negative for CD19 and obtained remission with chemotherapy. These findings suggest that increased osteoclastic bone resorption via stimulation with TNF‐α and IL‐6 may be mechanism causing PTHrP‐independent hypercalcemia in some patients with precursor B ALL lacking CD19 expression. Pediatr Blood Cancer 2007;49:990–993. © 2006 Wiley‐Liss, Inc.