<p>Lipidomes are thought to be associated with preeclampsia (PE). In addition, the immune response has been reported to play an important role in the development of PE. However, the causal relationship between the three remains unclear. We aimed to determine whether genetically predicted lipidomes, immunophenotypes, have a causal effect on PE, and also to explore whether immunophenotypes mediate the causal effect of lipidomes on PE. Two-step Mendelian randomization (MR) analysis, mainly using the inverse variance weighted (IVW) method, was performed to estimate the correlation between lipidomes, immunophenotypes, and PE and the potential effect of mediators. Bayesian analysis was also performed to improve the accuracy of the results. Finally, heterogeneity and horizontal polytropy tests were performed. The STROBE-MR checklist for the reporting of MR studies was used in this study. A total of 9 lipidomes and 25 immunophenotypes were found to be causally associated with the risk of PE, and mediation MR analyses identified HLA DR + Natural Killer %Natural Killer, HLA DR on B cell, and CD28 + CD45RA + CD8^dim T cell Absolute Count as mediators of the causal association between lipidomes and PE. Our MR study genetically suggests that lipidomes and immunophenotypes play an important role in the pathogenesis of PE, highlighting the potential mediating role of the three immunophenotypes, which contributes to a more in-depth understanding of the pathomechanisms of PE, thus providing new insights for the development of preventive and therapeutic strategies.</p>