BACKGROUND: The failure of specific types of human papillomaviruses (HPV) to raise effective immune responses may be important in the pathogenesis of cervical cancer, the second most common cancer in South African women. Polymorphisms of a number of cytokine genes have been implicated in inducing susceptibility or resistance to cancers caused by infectious agents owing to their role in determining host immune response. Polymorphisms of IL-10 and IFN-gamma genes are believed to influence the expression and/or secretion levels of their respective cytokines. METHODS AND RESULTS: In this study, women with histologically proven cancer of the cervix (n = 458) and hospital-based controls (n = 587) were investigated for bi-allelic -1082 (A/G) polymorphisms of IL-10 and the bi-allelic +874(A/T) polymorphisms of IFN-gamma. In addition, the distributions of the allelic frequencies were stratified in both the African and mixed race population groups of South Africa. We found striking differences in the allele distribution of IFN-gamma (X2 = 0.02) among the two ethnic groups. A significant increase in the allele distribution of the IFN-gamma AA genotype was found in the African group compared to the mixed population group (OR, 0.5; 95% CI, 0.2-1.0). For IL-10 there were no significant allelic differences between the two South African ethnic groups. Furthermore, when the ethnic groups were combined the IL-10 allelic frequencies in the combined South African data were similar to those observed in an Oriental population from Southern China and in an Italian population. However, the allele frequencies of the IFN-gamma genotype among the two South African ethnic groups were different when compared to an Italian Caucasoid group. While crude analysis of these data showed both statistically significantly increased and diminished risks of cervical cancer among high producers of INF-gamma and low producers of IL-10 respectively, these associations were no longer significant when the data were adjusted for confounding factors. CONCLUSION: These findings demonstrate a clear correlation between ethnicity and IFN-gamma polymorphism across different population groups. However, these differences in ethnicity and gene polymorphisms in the aforementioned cytokines are suggested not to influence the development of invasive cervical cancer but may represent an important susceptibility biomarker for other diseases and should be explored further.