DNA damage via radiation exposure and administration of chemotherapeutic agents induce apoptosis, which is a basic mechanism for non-surgical anti-cancer treatment. We analyzed ionizing radiation (IR)- or ultraviolet (UV)-induced apoptosis in human laryngeal carcinoma (HEp-2) and uterine cervical carcinoma (HeLa) cells, and found that HeLa cells were significantly more sensitive to both IR- and UV-induced apoptosis compared to HEp-2 cells, in spite of the same histological type and p53 status. The cyclin-dependent kinase (Cdk) inhibitor, p21Waf-1 was modified differently between the two cancer cell types, whereas p53 protein was induced in a similar manner after IR or UV treatment. IR steadily induced p21Waf-1 protein in HEp-2 cells, but not in HeLa cells. Additionally, p21Waf-1 protein recovered close to the basal level only in HEp-2 cells, although UV caused rapid, dramatic and caspase-independent reduction of p21Waf-1 protein in both cancer cells. Furthermore, overexpression of p21Waf-1 protein in these cells by transient transfection and in stable cell lines in a tetracycline-regulated system, rescued IR- and UV-induced apoptosis. Finally, suppression of p21Waf-1 protein using antisense oligodeoxynucleotide transfection facilitated UV-induced apoptosis in both HEp-2 and HeLa cells. We concluded that p21Waf-1 protein is modified independently of p53 and functions as an inhibitor of IR- as well as UV-induced apoptosis in squamous carcinoma cells.