Infection with high-risk human papillomavirus (HR-HPV) is a necessary but not a sufficient event in the development of cervical cancer, as most infections regress without intervention. Thus, genetic host factors and cellular immune responses could be potential modifiers for the risk of developing cervical cancer. In particular, p53 is considered as the most critical tumour suppressor gene and is involved in regulating cell division. The polymorphism on p53, which encodes either a proline or an arginine amino acid residue at codon 72, has been reported as a possible risk factor for cervical disease. This polymorphism has been shown to differentially affect the efficiency of degradation of p53 protein mediated by HR-HPV E6 oncoprotein. Women with histologically proven cancer of the cervix (n = 111) and hospital-based controls (n = 143) were included in this study. The patients and controls were from the Western Cape Province in South Africa. Genotyping of the p53 polymorphism was conducted using polymerase chain reaction and restriction fragment-length polymorphism method. The distributions of the allelic frequencies were stratified in both patients and controls into two South African ethnic population groups. In this study, we observed no association between the distribution of p53 polymorphism and susceptibility to cervical cancer in the Western Cape Province populations (P = 0.466). However, the frequency of the Pro/Pro residue at codon 72 was increased in the South African population when compared to Caucasians, Indians and Portuguese population groups. Notably, as the distribution of the Pro/Pro at codon 72 of p53 gene was significantly different (P < 0.05) between the control groups of South Africa and other population groups. This result suggests that ethnic disparity may influence the levels of p53 produced.