Hypercalcemia is a rare but potentially fatal complication during the management of childhood cancer. The treatment of severe hypercalcemia in children has not been clearly defined. The authors present a retrospective series of 16 children (11 boys and 5 girls) with severe hypercalcemia (>/=2.9 mmol/L) treated between 1997 and 2004 for malignancy. Median serum calcium level was 3.14 mmol/L. Hypercalcemia was present at the initial diagnosis of cancer (eight patients) or occurred during treatment (five patients) or during relapse (three patients). Three children had several episodes of hypercalcemia. All children were treated by hydration for a median of 7 days (range 2-12 days). Eight patients received intravenous pamidronate. The other treatments were adapted to the mechanism of hypercalcemia. Serum calcium levels were lowered to below 3 mmol/L after a median of 2 days and to below 2.7 mmol/L after a median of 4 days after starting treatment. Pamidronate was well tolerated apart from one case of multifactorial renal failure. Intravenous pamidronate is a safe and effective treatment for severe cancer-related hypercalcemia in children. Specific therapy must be initiated as soon as possible. Serum calcium levels must be monitored for a fortnight after administration of pamidronate due to the risk of hypocalcemia.