Azacitidine, used in the treatment of higher-risk myelodysplastic neoplasms, is a DNA methyltransferase inhibitor that modifies epigenetic regulatory programs. The efficacy of azacitidine varies among patients, with approximately 50% of patients failing to respond. However, whether epigenomic factors affect responses to azacitidine has not been investigated. We examined chromatin accessibility in bone marrow cells from 23 treatment-naive patients with higher-risk myelodysplastic syndrome, suggesting azacitidine response is strongly associated with distinct hematopoietic cell states. Chromatin-accessible regions in non-responders were enriched for myeloid progenitor signatures, whereas those in responders were enriched for T cell signatures. Notably, CD8 T cells from non-responders exhibited reduced chromatin accessibility at TBX/EOMES-binding sites, bridging T cell differentiation state and azacitidine response. These findings suggest that immune cell function contributes to the responses to hypomethylating agents in myelodysplastic neoplasms and that chromatin accessibility could be used to predict drug responses in high-risk myelodysplastic syndrome patients.