Despite evidence that protein kinases are regulators of apoptosis, a specific role for phosphatases in regulating cell survival has not been established. Here we show that α4, a noncatalytic subunit of protein phosphatase 2A (PP2A), is required to repress apoptosis in murine cells. α4 is a nonredundant regulator of the dephosphorylation of the transcription factors c-Jun and p53. As a result of α4 deletion, multiple proapoptotic genes were transcribed. Either inhibition of new protein synthesis or Bcl-x_L overexpression suppressed apoptosis initiated by α4 deletion. Thus, mammalian cell viability depends on repression of transcription-initiated apoptosis mediated by a component of PP2A.