Studies on DNA tumor viruses have suggested a link between p53 and pRB in the control of cell growth and apoptosis. We examined the role of pRB in the control of p53-mediated apoptosis in HeLa cells, in which the activities of p53 and members of the pRB family are very low. Transient overexpression of wild type (wt) p53 in HeLa cells induced apoptotic cell death. Importantly, coexpression of functional pRB resulted in significant protection of HeLa cells from p53-mediated apoptosis, without interfering with the transcriptional activity of wt p53. These results suggest that pRB, and possibly other pRB-related proteins, play a major role in the decision of whether cells respond to activated p53 by undergoing growth arrest or apoptosis. Our findings demonstrate a direct link between these two tumor suppressors in the control of cell growth and cell death.