BACKGROUNDKnee osteoarthritis (KOA) is a multifactorial condition affected by genetic and environmental factors. Studies have explored the relationship between IL-16 genetic polymorphisms and KOA risk, but findings have been inconclusive. This meta-analysis seeks to assess the association between IL-16 polymorphisms and KOA risk.METHODSA systematic literature search was conducted in several databases, including PubMed, Web of Science, EMBASE, SciELO, and CNKI, for studies published until June 1, 2024. Two independent researchers identified peer-reviewed articles in English, Portuguese, and Chinese using keywords related to "Knee Osteoarthritis" and "Interleukin 16." Relevant references were also manually reviewed for additional studies. Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated to assess the association strength. Additionally, minor allele frequencies (MAFs), Hardy-Weinberg equilibrium (HWE) data, heterogeneity, publication bias, and Newcastle-Ottawa scores (NOS) were evaluated.RESULTSThis analysis included 15 case-control studies, encompassing 1747 individuals with KOA and 1627 healthy controls. Within these studies, five investigated the genetic variations rs11556218 (584 cases, 542 controls), rs4778889 (583 cases, 543 controls), and rs4072111 (580 cases, 542 controls). The findings suggest that the IL-16 variants rs11556218 and rs4072111 may offer protection against KOA development, while no link exists between the rs4778889 variant and KOA susceptibility. The variability in IL-16 polymorphisms, particularly in Asian and Chinese populations, indicates different genetic associations with KOA risk. Strong results, supported by sensitivity analyses and the absence of significant publication bias, emphasize the influence of study methods on the relationship between these polymorphisms and KOA risk.CONCLUSIONSThe analysis of three polymorphisms-rs11556218, rs4778889, and rs4072111-shows varying associations with KOA. Rs11556218 and rs4072111 offer protective effects in non-Asian populations, while rs4778889 shows no significant association across cohorts. Notably, rs11556218 and rs4072111 do not correlate with KOA susceptibility in Asian and Chinese populations, suggesting ethnic differences in genetic influences on KOA.