Background This study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) at the microRNA target sequence inCXCR4and the susceptibility to knee osteoarthritis (KOA). Methods A total of 305 patients with KOA and 305 healthy controls were recruited into this study. The genotypes ofCXCR4rs1804029 and rs17848060 loci were analyzed. Results The susceptibility to KOA ofCXCR4rs1804029 G allele carriers was 1.33 times (95% CI: 1.09-1.54,P = .006) that of T allele carriers. The KOA susceptibility in individuals carrying T allele atCXCR4rs17848060 locus was 1.38 times that of individuals carrying A allele (95% CI: 1.17-1.57,P < .001). The G allele atCXCR4rs1804029 locus was the target of hsa-miR-146a-3p, while the A allele atCXCR4rs17848060 locus could be targeted by hsa-miR-20a-3p. The plasma level of hsa-miR-146a-3p was lower in rs1804029 G allele carriers than T allele carriers (P < .001), whereas plasma level of hsa-miR-20a-3p was higher in rs17848060 T allele carriers than A allele carriers (P < .001). Conclusion The SNPs at rs1804029 and rs17848060 loci inCXCR4were significantly associated with the susceptibility to KOA in Han Chinese population.