Recent studies have shown that arsenic trioxide (As(2)O(3)) can induce complete remission in patients with acute promyelocytic leukemia (APL). We tested the efficacy and safety of As(2)O(3) for the treatment of patients with APL who had relapsed from or become refractory to all-trans retinoic acid (ATRA) and conventional chemotherapy in a prospective study. As(2)O(3) at a dose of 0.15 mg/kg was administered until the date of bone marrow remission to a maximum of 60 days. In patients who achieved complete remission (CR), one additional course of As(2)O(3) was administered using the same dose for 25 days. Of 14 patients, 11 (78%) achieved CR. Six of 10 patients who achieved CR showed disappearance of PML-RARalpha transcript by RT-PCR assay. The duration of As(2)O(3)-induced CR ranged from 4 to 22 months (median, 8 months) at a median follow-up of 17 months. Adverse events included 13 electrocardiogram abnormalities (13 QTc prolongation, eight ventricular premature contraction, four nonsustained ventricular tachycardia and two paroxysmal supraventricular tachycardia), seven nausea and vomiting, four pruritus, three peripheral neuropathy, three fluid retention and one APL differentiation syndrome. Four patients received antiarrhythmic agents. Hyperleukocytosis developed in five patients and in three cytotoxic drugs were necessary. Other adverse events were relatively mild. As(2)O(3) treatment is effective and relatively safe in relapsed or refectory patients with APL. Cardiac toxicities in patients with QTc prolongation should be carefully monitored.