Human endogenous retroviruses (HERVs) form a substantial part of the human genome. However, most elements remain transcriptionally silent. Malignant transformation and epigenetic therapies may induce transcription of HERV elements. Such HERV elements could potentially trigger adaptive immune responses and provide targets for immunotherapy applications. Here, we evaluate the potential for T cell recognition of HERV elements in myeloid malignancies. We studied 66 HERV genes reported to retain transcriptional activity and generated a library of 1,169 potential antigenic HERV-derived peptides predicted for presentation by 4 HLA class I molecules. Through the use of DNA barcode-labeled MHC-I multimers, we identified CD8+ T cell populations recognizing 29 HERV-derived peptides, represented by 18 different HERVs. T cell recognition of HERVs was detected in half of the 34 patients analyzed and was significantly enhanced in patients compared to healthy donors. Patients with HERV-derived T cell reactivity demonstrated improved viral-antigen recognition following treatment, indicating that HERV-derived T cell recognition may contribute to the therapy-induced clinical improvement and immune reconstitution. In line with the T cell data, transcriptomic analyses revealed a significantly enhanced transcription of the HERVs in patients compared to healthy donors. DNA-demethylating therapy did not result in additional transcriptional enhancement of the HERVs evaluated for T cell recognition. Our study demonstrates substantial T cell recognition of HERVs in myeloid malignancies. These HERVs could serve as a reservoir of antigens potentially exploited as immunotherapeutic targets in malignancies with low mutational burden.