In the interleukin‐3 (IL‐3)‐dependent lymphoid cell line DA‐1, functional p53 is required for efficient apoptosis in response to IL‐3 withdrawal. Activation of p53 in these cells, by either DNA damage or p53 overexpression, results in a vital growth arrest in the presence of IL‐3 and in accelerated apoptosis in its absence. Thus, IL‐3 can control the choice between p53‐dependent cell‐cycle arrest and apoptosis. Here we report that the cross‐talk between p53 and IL‐3 involves joint control of pRb cleavage and degradation. Depletion of IL‐3 results in caspase‐mediated pRb cleavage, occurring preferentially within cells which express functional p53. Moreover, pRb can be cleaved efficiently by extracts prepared from DA‐1 cells but not from their derivatives which lack p53 function. Inactivation of pRb through expression of the human papillomavirus (HPV) E7 oncogene overrides the effect of IL‐3 in a p53‐dependent manner. Our data suggest a novel role for p53 in the regulation of cell death and a novel mechanism for the cooperation between p53 and survival factor deprivation. Thus, p53 makes cells permissive to pRb cleavage, probably by controlling the potential activity of a pRb‐cleaving caspase, whereas IL‐3 withdrawal provides signals that turn on this potential activity and lead to the actual cleavage and subsequent degradation of pRb. Elimination of a presumptive anti‐apoptotic effect of pRb may then facilitate conversion of p53‐mediated growth arrest into apoptosis.