THE Bcl-2-related protein, Bcl-x_L, has been shown to block apoptosis induced by a variety of stimuli^1–5 and to be a stronger protector against apoptosis than Bcl-2 under certain circumstances^2,5. Using site-specific mutagenesis, we show here that the amino-acid residues critical for protection of cells by Bcl-x_L against Sindbis virus-induced apoptosis are clustered within the Bcl-2-homology regions 1 and 2 (BH1 and BH2 regions). The residues necessary for Bcl-x_L function are not identical to those required for Bcl-2 function⁶. Although it has been suggested that heterodimerization between Bcl-x_L and Bax is essential for the anti-death activity of Bcl-x_L (refs 7,8), our results suggest that the interaction with Bax is not required for Bcl-x_L to exert its death-repressing activity. Specific mutations that disrupt the ability of Bcl-x_L to interact with Bax or Bak still preserve 70–80% of the anti-death activity of wild-type Bcl-x_L.