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Background: Observational epidemiological studies suggested that immunological dysregulation and inflammation play a significant role in the placental and renal dysfunction that leads to maternal hypertension. The immunophenotypes' possible causalities with hypertensive disease of pregnancy remain ambiguous. We performed two-sample Mendelian randomization (MR) analyses to comprehensively investigate the causal effect of immunophenotypes on hypertensive disorder of pregnancy (HDP)., Methods: The large-scale genome-wide association studies (GWASs) data on immunological traits was taken from public catalog for 731 immunophenotypes. The summarized GWAS data in 4 types of HDP were retrieved from FinnGen database, including 811,605 Finnish individuals. The primary analysis was the inverse variance weighted (IVW) method, supplemented by conducting sensitivity analysis. To confirm whether cardiovascular proteins mediated the causal effect of immune cells on HDP, we additionally executed a mediation MR study., Results: After looking into genetically predicted immunophenotype biomarkers, we discovered 14 highly correlative immunophenotypes and 104 suggestive possible factors. The IVW analysis indicated that HLA DR on myeloid DC, HLA DR on plasmacytoid DC, and HLA DR on DC had a significant association with pre-eclampsia/eclampsia (PE), whereas CD4 + CD8 dim AC and CD4 + CD8 dim % leukocyte were protective against gestational hypertension (GH). All of HDP in our study had no statistically significant impact on immune cells, according to reverse MR analysis. The mediating role of LOX-1between HLA DR on plasmacytoid DC and chronic hypertension prior to pregnancy was validated., Conclusion: This study showed that many immunophenotypes are implicated in HDP. Furthermore, the level of LOX-1 mediated the pathophysiology relationship between HLA DR on plasmacytoid dendritic cells and chronic hypertension prior to pregnancy., Competing Interests: Declarations Ethics approval and consent to participate The GWAS summary statistics for 731 immune traits are publicly available from the GWAS Catalog (accession numbers from GCST90001391 to GCST90002121). All participants signed informed consent to study protocols approved by the Sardinian Regional Ethics Committee (protocol no. 2171/CE). FinnGen research project is based on samples from Finnish biobanks and data from national health registers and applies the permissions to utilise the register data for research purposes from national authorities. All studies were conducted in accordance with the Declarationof Helsinki. All the GWAS statistics used in this study have been published and the ethics committee at each institutional review board has acquired the written informed consent of all participants. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)