Abstract: Objective To explore the relationship between systemic lupus erythematosus (SLE) and the risk of acute pancreatitis (AP) using two-sample Mendelian randomization (MR) analysis.Methods Genome-wide association study (GWAS) data for SLE and AP were obtained. Sensitive SNPs were selected for analysis, using single nucleotide polymorphisms (SNPs) as instrumental variables (IVs). Then, MR analysis was conducted using inverse variance weighted (IVW) and weighted median (WM) methods, and the odds ratio (OR) was calculated to evaluate the causal relationship between SLE and AP. The results were validated through sensitivity analysis.Results A total of 9 SNPs loci were included as IVs. Under the random effects model, the OR values estimated by IVW and WM methods were 1.089 (95%CI:1.047-1.133, P<0.001) and 1.079 (95%CI:1.025-1.136, P=0.004), respectively, indicating a positive causal relationship between SLE and AP. Cochran's Q test showed no significant heterogeneity among the included SNPs (P＞0.05). The MR-Egger regression intercept was -0.016 (P=0.355), suggesting that the results were not affected by pleiotropy at the genetic level. Leave-one-out analysis and funnel plots further confirmed the stability and reliability of the results.Conclusions There is a positive causal relationship between SLE and AP, and SLE patients present a significantly higher risk of developing AP.