Cyclin-dependent kinase (CDK) inhibitor p21(WAF1/CIP1(-/-))-null mice have an increased incidence of tumor formation. Here, we demonstrate that p21(WAF1/CIP1) is unstable in HeLa cells treated with siRNA duplexes that target PKCdelta. PKCdelta phosphorylates p21(WAF1/CIP1 )at a serine residue ((146)Ser) located in its C-terminal domain. In cells treated with 12-O-tetradecanoylphorbol 13-acetate, the levels of both p21(WAF1/CIP1) and its (146)Ser-phosphorylated form increased significantly. We also show that a substitution, resulting from a single nucleotide polymorphism (SNP) at (149)Asp found in certain cancer patients, strongly compromises PKCdelta-mediated phosphorylation at (146)Ser and results in cells that are relatively resistant to TNFalpha-induced apoptosis. Thus, post-translational phosphorylation of p21(WAF1/CIP1) is important from an apoptotic cell death, and may also have patho-physiological relevance for the development of human cancer.