Objective：To evaluate the association between the susceptibility of knee osteoarthritis（KOA） and the gene polymorphisms of interleukin-16 in Han population. Methods：A case-control design was employed in this study. A total of 150 patients di－agnosed with primary KOA and 147 controls matched for age，sex and body mass index of Han ancestry were enrolled. Periph－eral blood samples were collected，and the polymerase chain re－action and restriction fragment length polymorphism analysis were used to check the three single nucleotide polymorphisms in the interleukin-16（IL-16）gene. The results were verified by gene sequencing. Results：The genotypes and polymorphisms were distributed in line with the Hardy-Weinberg equilibrium in the case and control groups. The results of non-conditional logistic regression analysis in codominant model showed that T/G genotype（rs11556218） may be a risk factor（OR=2.06；95%CI=1.26 to 3.35；P=0.005），G/G genotype（rs11556218） may be another risk factor（OR=2.52；95%CI=1.10 to 5.74；P=0.005），C/T genotype（rs4072111） may be a risk factor（OR=2.45；95%CI=1.42 to 4.22；P=0.000）and T/T genotype（rs4072111） also increased the risk of KOA（OR=4.04；95%CI=1.06 to 15.37；P=0.000）. Linkage disequilibrium was found between loci rs11556218 and rs4778889（D’=0.63，R2=0.236）. Further stratification analysis by SNPstats based on phenotype showed that TTT may be a risk factor（OR=3.70；95%CI=1.57 to 8.72；P=0.003） and GCC may be another risk factor（OR=6.22；95%CI=2.37 to 16.33；P=0.000）. Conclusion：The genetic polymorphisms of IL-16 gene are one of risk factors associated with the susceptibility of knee osteoarthritis in the Chinese Han population.