We define a novel Bcl-x isoform, Bcl-x gamma, that is generated by alternative splicing and characterized by a unique 47 amino acid C-terminus. Bcl-x gamma is expressed primarily in thymocytes, where it may depend on an interaction between the TCR and host MHC products, and in mature T cells, where its expression is associated with ligation of the T cell receptor. Overexpression of Bcl-x gamma in T cells inhibits activation-induced apoptosis; inhibition of Bcl-x gamma, after stable expression of Bcl-x gamma antisense cDNA, enhances activation-induced apoptosis. In contrast to other Bcl-x isoforms, cells that fail to express Bcl-x gamma after CD3 ligation undergo programmed cell death, while activated T cells that express Bcl-x gamma are spared. Identification of Bcl-x gamma helps provide a molecular explanation of T cell activation and death after antigen engagement.