Lumbar disc herniation (LDH) is a common spinal disease. In recent years, an increasing number of observational studies have reported the impact of inflammatory factors on LDH. By conducting Mendelian randomization (MR) analysis on 91 inflammatory factors, it is possible to reveal their causal relationship with LDH, providing new insights for prevention and treatment strategies. In this study, a two-sample MR analysis was performed, using 91 inflammatory factors as exposure data, and LDH data from 2 different sources as outcome data. Subsequently, the most significant results from the inverse-variance weighted analysis were subjected to meta-analysis, with multiple corrections applied to the thresholds to ensure result accuracy. Finally, reverse causality MR analysis was conducted to validate the causal relationship between the identified positive inflammatory factors and LDH. Ninety-one cytokines were analyzed in relation to LDH using MR with data from the Finngen and UK Biobank databases. The inverse-variance weighted results from both analyses were then meta-analyzed, and multiple corrections were applied to the significance threshold of the meta-analysis results. Ultimately, only 1 cytokine, tumor necrosis factor-beta levels (genome-wide association study ID: GCST90274840), showed a significant association after the combined MR analysis and multiple corrections, with an odds ratio of 1.073 (95% confidence interval: 1.034-1.113, P = .0154). Furthermore, this positive cytokine did not display any reverse causality with LDH from either data source. Tumor necrosis factor-beta levels are a risk factor for LDH, potentially increasing the risk of developing the condition and exacerbating its symptoms.Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.