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The management of myelodysplastic syndrome (MDS) remains challenging. We performed a phase I/II study to evaluate the safety and efficacy of decitabine in patients with MDS in Japan. Patients with MDS with red cell transfusion dependence or 5–30% blasts in marrow and with an International Prognostic Scoring System score of intermediate-1 or higher were eligible. Patients received intravenous decitabine at 15 or 20 mg/m2 daily for 5 days every 4 weeks. A total of 37 patients were enrolled. Three patients received 15 mg/m2 and experienced no dose limiting toxicity during the first cycle. Thirty-four patients received 20 mg/m2. Grade 3 or greater non-hematologic toxicities included cerebral infarction (n = 1), subdural hematoma (n = 1), elevated blood glucose (n = 1), and pulmonary hypertension (n = 1). At 20 mg/m2, complete response, partial response, and hematologic improvement were observed in 7 (20.6%), 2 (5.9%), and 7 (20.6%) patients, respectively. Complete cytogenetic response was observed in 30% of evaluable 20 patients. The median number of cycles to clinical response was 4 (range 4–8), and duration of remission was 474+ days (range 294–598+). The 2-year rate of acute myeloid leukemia-free survival was 52%. Correlative studies revealed hypomethylation in multiple genes in peripheral blood cells after treatment. Hypomethylation was generally more profound in CD15 + peripheral blood cells, which reflects myeloid cells, than in peripheral blood mononuclear cells. In summary, decitabine was safe and demonstrated efficacy in Japanese patients with high-risk MDS. This trial was registered at ClinicalTrials.gov (NCT00796003).