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Background: To investigate the causal role of lipid in sepsis and determine the effect of lipid-lowering interventions on the disease. Methods: Two-sample Mendelian randomization analyses were conducted to evaluate the associations of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B and apolipoprotein A-I levels with risks for sepsis, and those of low-density lipoprotein cholesterol (HMGCR, PCSK9, NPC1L1), triglycerides (LPL, ANGPTL3, APOC3) and high-density lipoprotein cholesterol (CETP), apolipoprotein A-I (CETP), apolipoprotein B (HMGCR, PCSK9, NPC1L1, LPL, APOC3) with sepsis. Results: HMGCR-mediated low-density lipoprotein cholesterol and apolipoprotein B were associated with an increased risk of sepsis, with an odds ratio value of 1.4 (95% confidence interval (CI): 1.06-1.84, P = 0.017) and 1.41 (95% CI: 1.01-1.98, P = 0.046). CETP-mediated high-density lipoprotein cholesterol and apolipoprotein A-I were associated with a reduced risk of sepsis, with an odds ratio of 0.87 (95% CI: 0.82-0.92, P < 0.01) respectively and 0.84 (95% CI: 0.78-0.9, P < 0.01). Sensitivity analysis showed that the results were robust. Conclusion: HMG-CoA reductase inhibitors and CETP inhibitors may contribute to the prevention and treatment of sepsis. [ABSTRACT FROM AUTHOR]