Background <p>Toll-like receptor signaling molecules are involved in tumor associated inflammatory response. This study aims to investigate the role of Toll-like receptor signaling molecule gene polymorphisms in the risk of HPV-related cervical lesions.</p> Methods <p>A total of 352 study subjects, 178 women with cervical lesions and 174 women without cervical lesion were involved in a case-control study. Real-time polymerase chain reaction (real-time PCR) was used to detect HR-HPV genotypes. Genotyping of SNPs for MYD88 gene (rs7744) and TRAF3 gene (rs1131877, rs12435483, rs3803286, rs12147254) were performed by Sanger sequencing. The MYD88 and TRAF3 haplotype frequencies were analyzed using the HaploView 4.2 program. Gene-gene interactions were analyzed using the multifactor dimensionality reduction (MDR).</p> Results <p>The TRAF3 rs3803286 (A) variant allele (OR = 0.724, <i>p</i> = 0.045) and TRAF3 rs1131877 (TC) variant genotype (OR = 0.563, <i>p</i> = 0.023) were found to be associated with a significantly reduced risk of cervical lesions. rs3803286-HPV-16/18 was the best interaction model for the risk of cervical lesions (<i>p</i> = 0.0004).</p> Conclusion <p>TRAF3 rs3803286 and rs1131877 are potential biomarkers of susceptibility to cervical lesions.</p> Clinical trial number <p>Not applicable.</p>