Aim:Observational studies have suggested that the causal relationship between systemic lupus erythematosus (SLE) and the risk of cerebrovascular disorders (CVDs) remains uncertain. The objective of this study was to evaluate the potential genetic differences between SLE and CVDs patients.Material and Methods:This genetic association study conducted Mendelian randomization (MR) analyses on the derived exposures and outcomes from summary statistics of genome-wide association studies (GWAS). This study employed univariate MR (UVMR) analysis, multivariable MR (MVMR) analysis, and meta-analysis, using data from large genomic databases such as the UK Biobank, FinnGen, and OpenGWAS. These methods aim to overcome confounding factors by using genetic variants as instrumental variables to infer causal relationships.Results:The UVMR analysis revealed a genetic causal relationship between SLE and ischemic stroke, with a positive correlation (odds ratio [OR] 1.000367; 95% confidence interval [CI] 1.000074-1.00066; P =0.014). No evidence of a genetic causal relationship was found between SLE and other types of CVDs, including cerebral aneurysm, intracerebral hemorrhage, subarachnoid hemorrhage, stroke, and transient ischemic attack. MVMR analysis, after adjusting for confounders such as smoking and type 2 diabetes, confirmed the robustness of the association between SLE and ischemic stroke. Furthermore, a meta-analysis of multiple MR outcomes was conducted to verify the stability of the results (OR, 1.00037; 95% CI, 1.00008-1.00067).Conclusion:Our study enhances the understanding of the genetic basis between SLE and various CVDs, particularly suggesting a positive causal association between SLE and ischemic stroke, and we emphasize the need for further research.