Abstract The hypomethylating agents azacitidine and decitabine are standard therapy for myelodysplastic syndromes (MDS), and are often used to treat patients with acute myeloid leukemia (AML) unlikely to benefit from cytotoxic chemotherapy. Switching hypomethylating agents after treatment failure is common, but this approach is not well studied. We retrospectively reviewed data on 25 patients with MDS, MDS/myeloproliferative neoplasm (MDS/MPN) or AML who were treated with decitabine after primary or secondary azacitidine failure at the University of Maryland Greenebaum Cancer Center. Five patients with MDS or MDS/MPN achieved stable disease with decitabine, but no patient achieved complete or partial remission or hematologic improvement. Most patients discontinued therapy due to disease progression or death after a median of 2 cycles and median survival was 5.9 months after decitabine initiation. Based on our data, decitabine therapy after azacitidine failure is of little benefit beyond disease stabilization in some patients.