Background: autoimmune diseases (ADS) are associated with sepsis. This study aims to investigate the causalities between ADs and sepsis using Mendelian randomization (MR). Methods: we extracted single-nucleotide polymorphisms (SNPs) closely associated with 10 ADs, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D), multiple sclerosis (MS), inflammatory bowel disease (IBD), celiac disease (CD), psoriasis (PsO), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and ulcerative colitis (UC) from the GWAS. Two-sample MR analysis was conducted using GWAS data from the UK Biobank to assess the association between the liability of each ad and sepsis and sepsis-related 28-day mortality. The inverse variance-weighted (IVW) method was used as the primary analysis. If sig-nificant causal relationships are found (considering multiple comparisons) in the univariate MR analysis, multivariate MR (MVMR) analysis is performed to adjust for body mass index (BMI) and smoking. A series of sensitivity analyses were conducted to validate the robustness of the results. Results: after adjusting for multiple testing, MR analysis revealed that PSC patients are responsible for increased susceptibility to sepsis using the IVW method (OR:1.033, 95%CI:1.007-1.060, PFDR = 0.020). Further sensitivity analyses validated the robustness of the above association. Even after adjusting for BMI and smoking, the MVMR-IVW still displayed a positive correlation（OR:1.043, 95%CI:1.022-1.064, P-value for IVW = 3.32E-05） between PSC patients and susceptibility to sepsis. However, no significant causal relationship was observed between SLE, RA, T1D, MS, IBD, CD, PsO, PBC, and UC with susceptibility to sepsis or short-term death risk. Conclusions: our MR analysis revealed a genetic susceptibility of PSC to sepsis. However, no causal relationship was observed between SLE, RA, T1D, MS, IBD, CD, PsO, PBC, and UC with suscep-tibility to sepsis or short-term death risk. Keywords: autoimmune diseases; sepsis; primary sclerosing cholangitis; Mendelian randomization