Objective <p>To investigate the association between SMAD4 gene single nucleotide polymorphisms (SNPs) and the risk of human papillomavirus (HPV) infection and cervical cancer.</p> Methods <p>A case-control study was conducted, enrolling 342 cervical cancer patients as the case group and 342 healthy individuals from concurrent physical examinations as the control group. Genotyping of SMAD4 SNP loci rs34468925 and rs8084630 was performed using the imLDR SNP genotyping technique. HPV detection in the case group was performed via PCR-reverse dot hybridization. Statistical analysis and the online SHEsis software were employed to comprehensively evaluate the association between the rs34468925 and rs8084630 SNP loci, their haplotypes, and the risk of HPV infection and cervical cancer.</p> Results <p>No significant association was observed between the genotypes, alleles, genetic models (dominant and recessive), or haplotypes of the SMAD4 gene SNPs rs34468925 and rs8084630 and HPV infection risk in either group (<i>P</i> &gt; 0.05). rs8084630 showed no association with cervical cancer risk (<i>P</i> &gt; 0.05). However, the TT genotype, T allele, and recessive genetic model of rs34468925 were significantly associated with a reduced risk of cervical cancer (<i>P</i> &lt; 0.05). Additionally, the rs34468925 CT genotype may be associated with clinical pathological characteristics (tumor classification, distant metastasis) in cervical cancer patients (<i>P</i> &lt; 0.05).</p> Conclusion <p>The SMAD4 rs34468925 polymorphism shows no significant association with HPV infection but is inversely associated with cervical cancer risk and certain clinicopathological characteristics.</p>