Beyond human papillomavirus (HPV) infection, host genetic factors may contribute to cervical carcinogenesis. This study aims to test the hypothesis that CA-dinucleotide repeat polymorphism in the first intron of the interferon-gamma (IFN-gamma) gene is associated with HPV-initiated cervical carcinogenesis. A hospital-based case-control study including patients with low-grade squamous intraepithelial lesions (LSILs; n = 93), high-grade squamous intraepithelial lesions (HSILs; n = 123) and invasive carcinomas (n = 153) of the uterine cervix, as well as 1:1 age-matched controls, was conducted. The IFN-gamma genotype was determined by PCR and capillary electrophoresis with internal standards. HPV genotype was determined by consensus PCR and reverse line blot hybridization. Genotypes containing the 12 or 14 allele (12 or 14 CA repeats) were significantly more common in patients with HSILs than in controls (46% vs. 22%; OR = 3.0; 95% CI = 1.7-5.2; p < 0.0001). In contrast, genotypes containing 13 and 18 were significantly more common in controls than in patients with HSILs (76% vs. 53%; OR = 0.3; 95% CI = 0.2-0.6; p = 0.0001) or squamous cell carcinomas (74% vs. 63%; OR = 0.6; 95% CI = 0.4-1.0; p = 0.037). The frequency of the 12 and 14 genotypes increased significantly in accordance with the severity of cervical carcinogenesis (p(test for trend) = 0.0002), whereas the 13 and 18 genotypes showed the opposite trend (p(test for trend) = 0.007). Comparing IFN-gamma genotype and HPV status, 18-containing genotypes were more frequently found in HPV(+) LSILs, and 12-containing genotypes were less frequently found in HPV(+) HSILs. Compared with non-13 genotypes, 13 genotype HSILs were more frequently infected with HPV58 (70% vs. 45%) and less frequently infected with HPV18 (0% vs. 16%; p= 0.007). Genetic polymorphism of the IFN-gamma gene is associated with individual susceptibility to cervical carcinogenesis. This polymorphism correlates with HPV infection in a disease- and type-specific manner.