Zinc finger gene 217 (ZNF217) is a candidate gene of polycystic ovary syndrome (PCOS) which is vulnerable to ovarian hyperstimulation syndrome (OHSS). However, the relationship between ZNF217 and OHSS is largely unknown. Our study demonstrated that ZNF217 was mainly distributed in the granulosa cells of rat ovary. Significantly higher expression of ovarian ZNF217 was detected in OHSS rats, being consistent with serum 17β-estradiol concentration and ovarian aromatase. Moreover, OHSS rats also showed decreased ovarian TSP-1 mRNA, an acknowledged VEGF signaling suppressor. The same changes were detected in human granulosa cells and follicular fluid. Thus, the increased ZNF217 and decreased TSP-1 may participate in OHSS onset. In vitro experiment revealed that ZNF217 positively regulated E2 synthesis through promoting cAMP response element binding protein (CREB) and thereby CYP19A1 in KGN cells. Furthermore, ZNF217 negatively regulated TSP-1 in KGN cells while TSP-1 promoted claudin1 and inhibited nitric oxide (NO) in HUVECs and HAECs. Both of claudin1 and NO are responsible for the regulation of vascular permeability (VP). Therefore, we demonstrated that ZNF217 contributed to OHSS onset through promoting E2 synthesis and the increase of VP. Moreover, the increased ZNF217 and decreased TSP-1 provided new targets for the prevention or treatment of OHSS in the future.