The prognosis for patients with relapsed/refractory AML, secondary leukemia and AML in older adults is extremely poor. An appealing alternative approach to intensive cytotoxic chemotherapy is to induce apoptosis with a novel agent. There is in vitro evidence that arsenic trioxide (ATO) has anti-proliferative and pro-apoptotic effects on myeloid leukemia cell lines. To evaluate efficacy and toxicities of ATO, we conducted a phase II trial including subjects with relapsed/refractory or secondary AML or age > or = 65 years with de novo disease. Eleven subjects were entered with a median age of 77 years (56-90) and a median total dose of ATO of 415.55 mg (91.5-793) with a daily dose of 0.25 mg/kg. Median survival following the first dose of ATO was 2.25 months (0.4-19). Myelosuppression was the major adverse effect, most likely due to disease progression rather than drug-related. All subjects had progressive disease. There was no direct treatment-related mortality. Based on this study, we do not recommend single agent ATO as a treatment option for AML.