Apoptosis is an important but poorly understood mechanism of cell regulation. Growth factor deprivation can trigger apoptosis in a variety of cells, suggesting the existence of a signal transduction pathway responding to external signals and leading to apoptosis. Overexpression of the proto-oncogene bcl-2 can override these signals and block apoptosis, indicating that the bcl-2 protein (Bcl-2) is an important component of the apoptotic response. The identification of Bcl-2-binding proteins might help explain how Bcl-2 acts to regulate apoptosis. Here we use the yeast two-hybrid system to show that the human ras-related protein R-ras p23 (ref 16-18) binds to Bcl-2. This association is also detected in immunoprecipitates from human cell extracts. The association requires full-length Bcl-2 but the C-terminal 60 amino acids of R-ras p23 are sufficient for the interaction. These results provide evidence of a putative component of a signal transduction pathway involved in the regulation of apoptosis.