BACKGROUND: Interleukin-16 (IL-16), a pleiotropic cytokine, plays a fundamental role in inflammatory diseases. This study investigates the association between IL-16 polymorphisms and the risk of knee osteoarthritis (OA) in a Chinese population. METHODS: The IL-16 rs11556218, rs4072111, and rs4778889 polymorphisms were determined in 150 knee OA cases and 147 healthy controls through polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The results suggested that the variants in IL-16 gene rs11556218 site were associated with a decreased knee OA risk after adjusting for age, sex, BMI, and smoking and drinking status (TG vs. TT: OR, 0.69; 95% CI, 0.53-0.89; P = 0.006; GG vs. TT: OR, 0.64; 95% CI, 0.45-0.90; P = 0.042; dominant model: OR, 0.68; 95% CI, 0.29-0.87; P = 0.002; G vs. T allele: OR, 0.77; 95% CI, 0.66-0.90; P = 0.003). Similarly, subjects bearing the rs4072111 variant genotypes and alleles also had a lower susceptibility to knee OA compared with those bearing the wild-type (CT vs. CC: OR, 0.66; 95% CI, 0.53-0.83; P = 0.002; TT vs. CC: OR, 0.57; 95% CI, 0.40-0.82; P = 0.027; dominant model: OR, 0.65; 95%, CI 0.52-0.80; P <0.001; T vs. C allele: OR, 0.69; 95% CI, 0.58-0.81; P <0.001). Further, the C allele and the combined genotype (CC+CT) of rs4778889 were associated with a slightly decreased risk of knee OA. In addition, we found two high-risk haplotypes: TTT (OR, 3.70) and GCC (OR, 6.22). Finally, serum IL-16 levels of knee OA patients were significantly higher than those of controls (P = 0.001). CONCLUSIONS: Despite the small sample size, this is the first study suggesting IL-16 gene polymorphisms to be associated with the risk of knee OA.