Preeclampsia (PE) is a syndrome that occurs during pregnancy and affects more than 8 million mother-infant pairs each year. Most previous studies on the pathogenesis of PE have focused on the placenta. However, decidualization is the basis for placentation and subsequent development. The CRL4 (Cullin 4-RING E3 ubiquitin ligase) complex ubiquitinates and degrades substrates, while DCAF13 (DDB1 and CUL4-associated factor 13) is a component and substrate receptor of this complex, which recognizes and recruits the complex different substrates. DCAF13 plays a major role in the maintenance of follicles and the development of oocytes. However, its role in subsequent pregnancies remains unclear. In the present study, we first investigated DCAF13 levels in the decidua of PE patients and found that it is significantly lower than that of normal pregnant women. Second, we found that DCAF13 expression increases during decidualization, and reducing expression of DCAF13 by siRNA prevents decidualization. Third, in vivo experiments in mice further revealed that Dcaf13 expression increases with decidualization. Finally, we generated and found that uteri of pseudopregnant conditional Dcaf13 knockout mice fails to undergo decidualization. Therefore, we propose that DCAF13 plays a key role in decidualization. Abnormal expression of DCAF13 affects the decidualization process, which is likely involved in the occurrence and development of PE.