Objective:Observational epidemiological studies have shown a link between obesity and sepsis, but any causal relationship is not clear. Our study aimed to explore the correlation and causal relationship between body mass index and sepsis by a two-sample Mendelian randomization (MR).Methods:In large sample genome-wide association studies, single-nucleotide polymorphisms related to body mass index were screened as instrumental variables. Three MR methods, MR-Egger regression, weighted median estimator, and inverse variance-weighted, were used to evaluate the causal relationship between body mass index and sepsis. Odds ratio (OR) and 95% confidence interval (CI) were used as the evaluation index of causality, and sensitivity analyses were conducted to assess pleiotropy and instrument validity.Results:By two-sample MR, the inverse variance weighting method results suggested that increased body mass index was associated with an increased risk of sepsis (odds ratio 1.32; 95% CI 1.21–1.44;p= 1.37 × 10−9) and streptococcal septicemia (OR 1.46; 95% CI 1.11–1.91;p= 0.007), but there was no causal relationship with puerperal sepsis (OR, 1.06; 95% CI, 0.87–1.28;p= 0.577). Sensitivity analysis was consistent with the results, and there was no heterogeneity and level of pleiotropy.Conclusion:Our study supports a causal relationship between body mass index and sepsis. Proper control of body mass index may prevent sepsis.