Bcl-XS is a pro-apoptosis member of the Bcl2 family that has been shown to induce cell death and enhance chemosensitivity. We have investigated the effect of Bcl-XS overexpression on radiation sensitivity. Using a tetracycline-repressible system, we found that removal of tetracycline for 16 h induced Bcl-XS and reduced the surviving fraction of NIH 3T3 cells to 25%. However, radiation sensitivity was not significantly affected by Bcl-XS expression; the mean inactivation doses for Bcl-XS repressed and Bcl-XS induced cells were 2.7 ± 0.3 and 2.3 ± 0.1 Gy, respectively. We conclude that Bcl-XS induces cell death without affecting radiation sensitivity. These results suggest that mitochondrial pathways to apoptosis may not have a significant role in survival after irradiation.