The transcription factor c-Maf is critical for IL-4 production and the development of Th2 cells, which promote humoral immunity and protect against extracellular parasites. Yet, little else is known of c-Maf function in CD4 cells. Here, we identify a novel role for c-Maf in regulating susceptibility to apoptosis. Overexpression of c-Maf results in increased susceptibility of CD4 cells to apoptosis induced by multiple stimuli, including growth factor withdrawal, dexamethasone, irradiation, and TCR engagement. This effect is independent of Fas or p53; however, Bcl-2 expression is reduced in c-Maf Tg CD4 cells. Immunoprecipitation and Western blot analyses demonstrate that c-Maf-c-Myb complex formation is enhanced among T cells from c-Maf Tg mice compared to non-Tg littermates following TCR engagement. Unlike non-Tg T cells, c-Myb binding to the Bcl-2 promoter is not detectable in c-Maf Tg T cells by chromatin immunoprecipitation. In reporter assays, Bcl-2 promoter activity is reduced by c-Maf in a dose-dependent manner. Furthermore, transgene-mediated Bcl-2 expression corrects the apoptosis defect observed among c-Maf Tg CD4 cells. These data suggest that c-Maf can interact with c-Myb to reduce Bcl-2 expression, thereby limiting CD4 cell survival following TCR engagement. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.