Abstract: Background　Studies have found that inflammatory factors are closely associated with the progression of osteoarthritis, but the relationship between inflammatory factors and osteoarthritis (OA) remains unclear. Objective　To analyze the causal relationship between 91 inflammatory factors and OA using Mendelian randomization (MR). Methods　Genome-wide association study (GWAS) data of 91 inflammatory factors and OA were obtained. The inverse variance weighted method (IVW) was used as the main method, and four other methods, including MR-Egger regression, were used as supplementary methods to evaluate the causal effect. Sensitivity analysis was conducted using Cochran Q, MR-PRESSO, MR-Egger intercept test, and leave one-out analysis. Results　MR analysis identified five inflammatory factors significantly associated with OA (all P＜0.05): chemokine ligand 4 (CCL4), chemokine ligand 23 (CCL23), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), chemokine ligand 11 (CCL11), and interleukin-20 receptor α (IL-20Rα). The IVW method yielded the following odds ratios (ORs) and 95% confidence intervals (CIs): CCL4 (OR=1.002 6, 95% CI: 1.000 8-1.004 5), CCL23 (OR=0.997 7, 95% CI: 0.995 5 - 0.999 8), TRAIL (OR=0.996 9, 95% CI: 0.994 4 - 0.999 3), CCL11 (OR=0.996 9, 95% CI: 0.993 9 - 0.999 9), and IL-20Rα (OR=0.995 8, 95% CI: 0.991 8 - 0.999 8). Sensitivity analyses showed no evidence of heterogeneity (Cochran's Q test), outliers (MR-PRESSO test), or horizontal pleiotropy (MR-Egger intercept test), with leave-one-out analysis further confirming the robustness of the results. Conclusion　MR analysis supports potential causal relationships between these inflammatory factors and OA, identifying CCL4 as a risk factor and CCL23, TRAIL, CCL11, and IL-20Rα as protective factors.