Objective To investigate the expression and clinical significance of signal peptide⁃CUB⁃EGF⁃ like domain⁃containing protein 2（SCUBE2）in peripheral blood and placenta of pregnant women with preeclampsia. Methods A total of 58 patients with preeclampsia who were hospitalized for delivery in Hospital affiliated to Xuzhou Medical University from June 2021 to June 2022 were selected，including 30 patients with early⁃onset preeclampsia（weeks of onset < 34 weeks）and 28 patients with late⁃onset preeclampsia（weeks of onset ≥ 34 weeks）； another 30 pregnant women with full⁃term normal delivery were selected as the control group. Serum samples were collected from pregnant women before admission and fresh placental tissue samples during delivery. The expression levels of SCUBE2 and VEGFR2 in the serum of the three groups were detected by ELISA. The localization and expression of SCUBE2 in the placental tissues of the three groups were detected by immunohistochemistry. The expression levels of SCUBE2 and VEGFR2 in the placental tissues of the three groups were detected by Western blot assay and real⁃time PCR（RT⁃qPCR）assay. Results Immunohistochemistry showed that SCUBE2 was mainly expressed in placental syncytiotrophoblasts and placental vascular endothelial cells. The expression level of pre⁃ eclampsia group was lower than that of control group，and the expression level of early ⁃onset preeclampsia group was lower than that of late⁃onset preeclampsia group；The results of Western⁃blot and RT⁃qPCR showed that there were significant differences in the relative expression levels of SCUBE2 and VEGFR2 protein and mRNA in the pla⁃centa of the three groups（P < 0.05）. ELISA showed that the expression levels of SCUBE2 and VEGFR2 in serum of pregnant women in the three groups were significantly different（P < 0.05）. The preeclampsia group was lower than the control group，and the expression level in the early ⁃onset preeclampsia group was lower than that in the late⁃onset preeclampsia group（P < 0.05），And there was a positive correlation between serum SCUBE2 and VEGFR2 expression in preeclampsia group. Conclusion The decreased expression of SCUBE2 and VEGFR2 in maternal serum and placental tissue may be related to the occurrence and development of preeclampsia.