The safety and efficacy of azacitidine (5-day schedule) were assessed in a multicenter study in 40 patients (median age 72 years) with acute myeloid leukemia (AML) medically unfit for (n = 20) or resistant to chemotherapy (n = 20) from April to October 2008. Median marrow blasts were 42%. After a median follow-up of 13 months, response (complete remission [CR]/partial remission [PR]/hematologic improvement [HI]) was 50% and 10% in newly diagnosed and relapsed/refractory patients, respectively (p = 0.008). Median time-to-response was 2.5 months with a median duration of 5.9 months. Median survival was not reached for responders versus 3.8 months for 15 (38%) patients with stable disease (p < 0.045). High-risk cytogenetics was associated with inferior survival (p = 0.05). Lower marrow blasts on day 15 of cycle 1, irrespective of pretreatment count, predicted subsequent response (p = 0.01). Azacitidine is active and well tolerated in elderly patients with newly diagnosed AML.