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OBJECTIVE: Emerging evidence indicates a correlation between inflammation and liver cancer. However, the causality remains elusive. MATERIALS AND METHODS: In this study, we performed a two-step, two-sample Mendelian randomization (MR) analysis to understand the causal associations of C-reactive protein and other inflammatory regulators with liver cancer. Summary-level data for genetic variants associated with inflammation, and liver cancer were extracted from the largest genome-wide association studies. The principal MR analysis was performed by using an inverse-variance weighted (IVW) method with a random-effects model. Besides, MR-egger and weighted median were used as sensitivity analyses. RESULTS: Using the IVW method, the only association was between the levels of TRAIL and a higher risk of liver cancer (Odds ratio: 0.699, 95% Confidence interval: 0.519-0.941, p = 0.018). Most importantly, the sensitivity analysis also revealed similar results. No other causal associations were observed between the genetically predicted systemic inflammatory regulators and the risk of liver cancer. CONCLUSIONS: This study provides genetic evidence of relationships between systemic inflammatory factors and liver cancer. Interventions that target TRAIL levels may be promising targets for the development of cancer therapies for liver cancer.