Postulated roles for p21(Waf1/Cip1/Sdi1) (p21) in DNA repair and apoptosis remain controversial. Studies suggest both stimulatory and inhibitory effects of p21 in DNA repair. p21 has also been implicated in induction or protection from apoptosis. Using the tetracycline inducible expression system, we studied the role of p21 in DNA repair and apoptosis in wild-type p53 deficient DLD1 colorectal carcinoma cells. These cells displayed marked heterogeneity in their ability to tolerate higher levels of exogenous p21. The majority of the p21 overexpressing cells grew slower and did not exhibit apoptotic phenotype, some cells underwent apoptotic death within 5-8 days following p21 induction while other became giant cells prior to undergoing cell death. Induction of p21 transgene neither sensitized to nor protected from adriamycin-induced acute cell death. p21 also did not alter the clonogenic survival following adriamycin treatment. Clonogenic survival after u.v.-irradiation was, however, increased when p21 expression was transiently induced a few hours before and after u.v.-irradiation. Consistent with its effect on clonogenic survival, p21 also enhanced the cellular capacity to repair three different exogenously introduced u.v.-damaged reporter plasmids. Taken together our results demonstrate that p21 may modulate the nucleotide excision repair process to facilitate the repair of u.v.-type DNA damage even in the absence of wild-type p53.