Abstract Introduction Hypertensive disorders of pregnancy (HDPs; including preeclampsia/eclampsia and gestational hypertension) are a leading cause of maternal and neonatal morbidity and mortality worldwide, and women with HDPs have increased long-term risk for cardiovascular morbidity and mortality. Purpose Here, we leveraged Mendelian randomization (MR) to identify novel therapeutic targets for gestational hypertension and preeclampsia/eclampsia and HDP-associated cardiovascular disease. Methods Genetic instruments were constructed for 90 proteins that were measured using the Olink CVD-I assay, chosen due to their previous associations with cardiovascular disease. We only included cis-protein quantitative trait loci (cis-pQTLs; variants at P≤5x10-4 within 200kb of the protein-encoding region) to minimize potential horizontal pleiotropy. Cis-pQTLs were clumped at R²≤0.4, based on previous literature. Primary analyses used the inverse-variance weighted method adjusted for residual correlation between variants. We performed multiple sensitivity analyses, including clumping at different R² thresholds, using different MR methods, and testing for opposite direction of effects. Proteins robust to sensitivity analyses were selected for phenome-wide association studies (PheWAS) to investigate potential non-HDP-related effects. Results Seventy-five of 90 proteins had at least one valid cis-pQTL. We identified ten proteins associated with either gestational hypertension (CCL4, CD40, ECP, Galectin-3, KIM-1, MMP-12, NT-proBNP, and ST2) or preeclampsia/eclampsia (cystatin B, ECP, HSP27, and ST2) with a false discovery rate <0.05 (Figure 1). Four proteins (CD40, ECP, galectin-3, NT-proBNP) were robust to sensitivity analyses for gestational hypertension, while three proteins (cystatin B, ECP, HSP27) were robust for preeclampsia/eclampsia (Figure 2). PheWAS of genetic instruments suggested that non-HDP-related (i.e., "off-target") effects would predominantly be beneficial for ECP (three beneficial vs. one adverse non-HDP-related associations), galectin-3 (thirty-one vs. seven), and HSP27 (ten vs. two). Conclusions We identified putative causal associations of six cardiovascular disease-related proteins with gestational hypertension and/or preeclampsia/eclampsia. These findings call for further investigation into the preventive and therapeutic potential of these proteins.Figure 1Figure 2