Genital infection with the oncogenic human papillomavirus is the necessary cause of cervical cancer and of a large fraction of vulvar cancers. The toll-like receptor and the nuclear factor κB (NF-κB) signaling pathways have been implicated in inflammation, autoimmune disease and cancer, but whether common nucleotide variation in these pathways is associated with the risk of cervical and vulvar cancers has received little study. Using data from a population-based case-control study of cervical and vulvar cancers, we genotyped 205 single nucleotide polymorphisms (SNPs) in and around 32 candidate gene regions within these pathways. Gene-based analyses were used to estimate the associations between individual gene regions and the risk of cervical and vulvar cancers. Odds ratio (OR) and 95% confidence intervals (CI) were calculated to assess the risk of cervical and vulvar cancers for each SNP. p-Values were adjusted for multiple testing. A total of 876 cervical cancer cases, 517 vulvar cancer cases and 1,100 controls were included in the analysis. The TNF region was significantly associated with the risks of cervical cancer (gene-based p-value: 2.0 × 10(-4) ) and vulvar cancer (gene-based p-value: 1.0 × 10(-4) ). The rare allele (A) of SNP rs2239704 in the 5\' UTR of the LTA gene was significantly associated with increased risks of cervical cancer (OR=1.31, 95% CI: 1.15-1.50; adjusted p-value: 0.013) and vulvar cancer (OR=1.51, 95% CI: 1.30-1.75; adjusted p-value: 1.9 × 10(-5) ). These findings add to the evidence of the importance of the immune system in the etiology of cervical and vulvar cancers.