Engagement of the IFN-αβ receptor initiates multiple signaling cascades, including activation of the STAT. In this study, we demonstrate that IFN-αβ, although antiproliferative in wild-type CD4+ or CD8+ T cells, act as strong mitogens on their STAT1−/− counterparts. Furthermore, IFN-αβ exert little effect on apoptosis in wild-type cells, but are potent survival factors in the absence of STAT1. The antiapoptotic response in the absence of STAT1 is predominantly mediated by STAT3, and to a lesser extent by STAT5A/B. In contrast, the mitogenic IFN-αβ response gained through the absence of STAT1 is only marginally affected when STAT5A/B expression is also abrogated, but is completely dependent on STAT3 activation. These findings provide the first evidence for a function of STAT3 and STAT5A/B in the IFN-αβ response, and support a model in which the IFN-αβ receptor initiates both pro-and antiapoptotic responses through STAT1, and STAT3 and STAT5A/B, respectively.