Abstract As the infectious agent causing human adult T-cell leukemia (ATL), the human T-cell leukemia virus type 1 (HTLV-1) virus spreads in vivo primarily by cell-to-cell transmission. However, the factors that determine its transmission efficiency are not fully understood. The viral genome encodes the HTLV-1 bZIP factor (HBZ), which is expressed in all ATL cases and is known to promote T-cell proliferation. In this study, we investigated the hypothesis that HBZ also influences the survival of T cells. Through analyzing the transcriptional profile of HBZ-expressing cells, we learned that HBZ suppressed transcription of the proapoptotic gene Bim (Bcl2l11) and that HBZ-expressing cells were resistant to activation-induced apoptosis. Mechanistic investigations into how HBZ suppresses Bim expression revealed that HBZ perturbs the localization and function of FoxO3a, a critical transcriptional activator of the genes encoding Bim and also Fas ligand (FasL). By interacting with FoxO3a, HBZ not only attenuated DNA binding by FoxO3a but also sequestered the inactive form of FoxO3a in the nucleus. In a similar manner, HBZ also inhibited FasL transcription induced by T-cell activation. Further study of ATL cells identified other Bim perturbations by HBZ, including at the level of epigenetic alteration, histone modification in the promoter region of the Bim gene. Collectively, our results indicated that HBZ impairs transcription of the Bim and FasL genes by disrupting FoxO3a function, broadening understanding of how HBZ acts to promote proliferation of HTLV-1–infected T cells by blocking their apoptosis. Cancer Res; 74(1); 188–200. ©2013 AACR.