Arsenic trioxide (ATO) induces remission in 85% of adults with refractory acute promyelocytic leukemia (APL). We conducted a phase 1 trial of ATO in children (median age 13 y, range, 2-19) with refractory leukemia. ATO was administered intravenously over 2 hours, 5 d/wk for 20 doses/cycle. Patients with APL (n=13) received 0.15 mg/kg per day, and patients with other types of leukemia received 0.15 mg/kg per day (n=2) or 0.2 mg/kg per day (n=4). Nineteen of the 24 enrolled patients were fully evaluable for toxicity. At 0.15 mg/kg per day, 2 of 15 patients experienced dose-limiting corrected QT interval (QTc) prolongation, pneumonitis, or neuropathic pain. At 0.2 mg/kg per day, 2 of 4 patients had dose-limiting QTc prolongation or pancreatitis. Non-dose-limiting toxicities included elevated serum transaminases, nausea, vomiting, abdominal pain, constipation, electrolyte imbalance, hyperglycemia, dermatitis, and headache. At 0.15 mg/kg per day, the median (range) plasma arsenic maximum concentration (Cmax) was 0.28 microM (0.11-0.37 microM) and at 0.2 mg/kg per day, Cmax was 0.40 and 0.46 microM; area under the concentration times time curve (AUC0-24) was 2.50 microM-hr (1.28-3.85 microM-hr) and 4.37 microM-hr and 4.69 microM-hr, respectively. Morphologic complete response (CR) was achieved in 85% of patients with APL; no responses were observed in non-APL patients. ATO is well-tolerated in children at the recommended dose of 0.15 mg/kg per day. The response rate in children with relapsed APL is similar to the response rate in adults. This trial was registered as #NCT00020111 at www.ClinicalTrials.gov.