Human T cell leukemia virus (HTLV) is the causative agent of adult T cell leukemia (ATL), an aggressive and fatal leukemia of CD4+ T lymphocytes in which interferon regulatory factor-4 (IRF-4) becomes constitutively expressed, concomitant with major alterations in host gene expression. When constitutively expressed in uninfected T lymphocytes, IRF-4 caused reduced expression of critical DNA repair genes, including Rad51, XRCC1, Ung1, RPA, and proliferative cell nuclear antigen (PCNA), a transcriptional phenotype with striking similarities to the profile observed in HTLV-infected T lymphocytes. Concomitant with the inhibition of gene expression and defects in the DNA repair pathways, increased sensitivity of T lymphocytes to various genotoxic stresses that challenged all major DNA repair pathways were detected. Together, these results support a role for IRF- 4 in the repression of DNA repair activity and an increase in the risk of mutations. IRF-4 may thus represent a previously unidentified endogenous transcriptional repressor of DNA repair mechanisms.