The usefulness of the arginine (Arg) residue at codon 72 of the p53 tumor suppressor gene as a marker for the risk of cervical cancer remains unclear. Studies to date have focused mainly on Caucasian subjects despite marked ethnic variations in both the p53 polymorphism and the frequency of cervical carcinoma. Furthermore, not all studies have taken into account the type of human papillomavirus (HPV) infection present. In this study, undertaken at King Edward VIII Hospital, Durban, South Africa, we determined the p53 codon 72 status in 281 black South African women with cervical cancer and 340 ethnically matched healthy control subjects. In addition, HPV DNA was confirmed in 190 cervical tumors and the viral type determined. Results showed that overall more cancer patients than control subjects had an Arg allele at codon 72 with respect to both genotype and allelotype (P < 0.05). A significantly higher (P < 0.001) Arg allele frequency (55%) was also observed in patients whose tumors contained low or intermediate risk HPV DNA compared with control subjects (31%); the Arg homozygosity rate was 34% and 9% in patients and controls, respectively (P < 0.001). In contrast, patients harboring HPV 16/18 infections showed no differences in p53 status compared with controls. It would appear that, in the absence of HPV 16/18 infections, the Arg allele at codon 72 of the p53 tumor suppressor gene may constitute a risk factor for carcinogenesis of the cervix.