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 function(6), 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).