Bcl-2 is the best characterized inhibitor of apoptosis, although the molecular basis of this action is not fully understood. Using a protein interaction cloning procedure, we identified a human gene designated as bis (mapped to chromosome 10q25) that encoded a novel Bcl-2-interacting protein. Bis protein showed no significant homology with Bcl-2 family proteins and had no prominent functional motif. Co-immunoprecipitation analysis confirmed that Bis interacted with Bcl-2 in vivo. DNA transfection experiments indicated that Bis itself exerted only weak anti-apoptotic activity, but was synergistic with Bcl-2 in preventing Bax-induced and Fas-mediated apoptosis. These results suggest that Bis is a novel modulator of cellular anti-apoptotic activity that functions through its interaction with Bcl-2.