Several caspase-cleaved forms of the retinoblastoma protein have been described. Here, we compared the effect of full-length Rb versus the truncated p76(Rb) and p100(Rb) proteins on cell death regulation in five human cell lines. Interestingly, we observed that p76(Rb) triggers cell death in all tested cell lines and that p100(Rb) protects two cell lines against etoposide or TNF-alpha-induced cell death, whereas full-length Rb has no apoptotic effect. These results show that truncated forms of Rb can have specific activities in the regulation of cell death. They also suggest that caspase cleavage of Rb should not be simply assimilated to a degradation process. Finally, we show that cell death induced by p76(Rb) is Bax-dependent and is diminished by Bcl-2 overexpression or by caspase inhibition and that p100(Rb) could inhibit cell death by decreasing both p53 stability and caspase activity. (c) 2010 Elsevier Inc. All rights reserved.