Treatment of advanced-phase chronic myeloid leukemia (CML) remains unsatisfactory. Single-agent tyrosine kinase inhibitors have modest and short-lived activity in this setting. We conducted a phase I/II study to determine safety and efficacy of the combination of dasatinib and decitabine in patients with advanced CML. Two different dose schedules were investigated with a starting decitabine dose of either 10mg/m2 or 20mg/m2 daily for 10 days plus dasatinib 100 mg daily. The target dose level was decitabine 10mg/m2 or 20mg/m2 daily for 10 days plus dasatinib 140 mg daily. Thirty patients were enrolled, including 7 with accelerated-phase CML, 19 with blast-phase CML, and 4 with Philadelphia-chromosome positive acute myeloid leukemia. No dose-limiting toxicity was observed at the starting dose level with either schedule. Grade ≥3 treatment emergent hematological adverse events were reported in 28 patients. Thirteen patients (48%) achieved a major hematologic response and 6 (22%) achieved a minor hematologic response, with 44% of these patients achieving a major cytogenetic response and 33% achieving a major molecular response. Median overall survival (OS) was 13.8 months, with significantly higher OS among patients who achieved a hematologic response compared to non-responders (not reached versus 4.65 months; p<0.0001). Decitabine plus dasatinib is a safe and active regimen in advanced CML. Further studies using this combination are warranted. This article is protected by copyright. All rights reserved.