ObjectiveTo investigate the causal association between metabolic syndrome (MetS) components and osteoarthritis of the knee (KOA) by using Mendelian randomization analysis. MethodsThe genome-wide association study database (GWAS) was mined, in which the exposure factors were MetS components, namely waist circumference (WC) level, triglyceride (TG) level, high-density lipoprotein cholesterol (HDL-C) level, hypertension (HBP), and type 2 diabetes (T2DM), and the outcome factor was KOA. Mendelian randomization analysis was performed using regression models of inverse-variance weighted (IVW), MR-Egger, Simple Mode, Weighted Median, and Weighted Mode methods. ResultsIVW showed a causal relationship between WC level and KOA with a positive correlation (OR=3.088, 95%CI 2.574 to 3.704, P<0.01), and HDL-C level had a causal relationship with KOA with a negative correlation (OR=0.877, 95%CI 0.779 to 0.989, P<0.05). IVW did not show a causal relationship between TG levels, HBP, and T2DM with KOA (P>0.05). The results of the ME-Egger intercept test were not multiplicative (P>0.05), indicating that Mendelian randomization was a valid method for causal inference in this study. ConclusionCentral obesity and low HDL-C disorder are independent risk factors for KOA. The causal relationship between TG level, HBP, and T2DM with KOA is still uncertain.