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-a-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.