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Chronic myelomonocytic leukemia (CMML) is an uncommon neoplastic hematological disorder, typically affecting the elderly and characterized by a marked clinical heterogeneity and a remarkable propensity for transformation into acute myeloid leukemia. Hypomethylating agents represent the most innovative management approach in this difficult setting. At our institution, between 2010 and 2012, we have treated with azacitidine 10 CMML patients with a median age of (62–86) 75 years. An overall response rate of 70% was achieved without remarkable toxicities; in particular, most therapy-induced side effects were managed on outpatient basis. With a median follow-up of 22 (11 – 44) months, 6 patients are alive and 4 of them continue to receive the treatment; the median survival from the start of therapy was 22 months. In conclusion, also in the light of our encouraging experience, azacitidine can offer new chances of treatment also in the difficult setting of elderly CMLL.