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Resistance to platinum-based chemotherapy is one of major causes of therapy failure and tumor recurrence in ovarian cancer patients. However, the molecular mechanism of platinum resistance is not fully understood. Here, we compared gene expression between cisplatin-sensitive and -resistant ovarian cancer cells using gene expression microarray analysis and found the significantly up-regulated expression of SERPINE1 encoding plasminogen activator inhibitor-1 (PAI-1), a serine protease regulating the fibrinolysis and extracelluar matrix, in cisplatin-resistant ovarian cancer cells. The correlation of high PAI-1 expression with low cisplatin sensitivity was confirmed in ovarian cancer cells. PAI-1 overexpression in ovarian cancer cells significantly decreased the sensitivity to cisplatin, whereas PAI-1 down-regulation by SERPINE1 siRNA or PAI-1 inhibitor increased cisplatin sensitivity. PAI-1 inhibited cisplatin-induced apoptosis in ovarian cancer cells by suppressing reactive oxygen species (ROS) production and DNA damage. PAI-1 also decreased cisplatin-induced ferroptosis through the upregulation of GPX4 levels. Furthermore, Kaplan-Meier survival analysis using TGGA data demonstrated that high PAI-1 expression was significantly associated with shorter platinum-free survival of patients with ovarian cancer. Collectively, these results illustrate that PAI-1 promotes cisplatin resistance in ovarian cancer cells by inhibiting ROS-mediated apoptosis and ferroptosis, suggesting that targeting PAI-1 increases the sensitivity to cisplatin in ovarian cancer. Citation Format: Mi Jeong Kwon, Ha Yeong Chae, So Young Lee, Shin Ung Kang, Tae Woong Jung, Soo Youn Cho, Jinil Han, Hyojin Jeong, Chang Ohk Sung, Young Kee Shin. Plasminogen activator inhibitor-1 (PAI-1) promotes cisplatin resistance in ovarian cancer cells by inhibiting ROS-mediated apoptosis and ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1684.