ObjectiveEmerging evidence suggests an increased prevalence of coronavirus disease 2019 (COVID-19) in patients with systemic lupus erythematosus (SLE), the prototype of autoimmune disease, compared to the general population. However, the conclusions were inconsistent, and the causal relationship between COVID-19 and SLE remains unknown.MethodsIn this study, we aimed to evaluate the bidirectional causal relationship between COVID-19 and SLE using bidirectional Mendelian randomization (MR) analysis, including MR-Egger, weighted median, weighted mode, and the inverse variance weighting (IVW) method.ResultsThe results of IVW showed a negative effect of SLE on severe COVID-19 (OR = 0.962,p= 0.040) and COVID-19 infection (OR = 0.988,p= 0.025), which disappeared after Bonferroni correction. No causal effect of SLE on hospitalized COVID-19 was observed (OR = 0.983,p= 0.148). In the reverse analysis, no causal effects of severe COVID-19 infection (OR = 1.045,p= 0.664), hospitalized COVID-19 (OR = 0.872,p= 0.109), and COVID-19 infection (OR = 0.943,p= 0.811) on SLE were found.ConclusionThe findings of our bidirectional causal inference analysis did not support a genetically predicted causal relationship between SLE and COVID-19; thus, their association observed in previous observational studies may have been caused by confounding factors.