The tumor suppressive effect of p53 is believed to be rooted in its two primary functions: the implementation of cellular growth arrest and the execution of apoptotic cell death. While p53-regulated expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) appears to be central for the implementation of G1 arrest, the participation of p21(Waf1/Cip1) in p53-triggered cell death remains controversial. In the present study, overexpression of p53 in human melanoma SK-MEL-110 cells through use of an adenoviral expression vector (AdCMV.p53) was found to result in apoptosis, while similar infection of primary vascular smooth muscle cells (VSMC) instead resulted in a moderate inhibition of growth. Expression of p21(Waf1/Cip1) was strongly elevated in VSMC, but showed little change in SK-MEL-110 cells, although expression of another p53-regulated gene (GADD45) was comparable in both AdCMV.p53-infected cell types. Evidence that p21(Waf1/Cip1) expression may be required for surviving p53-induced cell death was further supported by the finding that p53 overexpression was highly toxic for p21-deficient mouse embryonal fibroblasts (p21-/- MEFs). In both SK-MEL-110 and p21-/- MEFs, adenovirus-driven ectopic expression of p21(Waf1/Cip1) resulted in a substantial protection against p53-induced apoptosis, indicating that p21(Waf1/Cip1) rescued cells from a path of programmed cell death to one of enhanced survival.