[Abstract] Objective: To explore the mechanism of TRIM21 regulating the proliferation of ovarian cancer cells and the resistance of PARP inhibitors by activating Wnt/β-catenin signaling pathway. Methods: Eight pairs of ovarian cancer tissues and cervical epithelial tissues that surgically removed at Yan'an People's Hospital from January 2018 to January 2019 were collected for this study. And the tissues were classified into resistant group and non-resistant group (4 case/group) according to whether the patients were resistant to PARP inhibitor (nilapanib). Ovarian cancer cell lines CAOV3, SKOV3, OVCAR3, ES-2, HO8910, A2780 and OV2008 were also collected for this study. qPCR and Western blotting (WB) were used to detect the expression levels of TRIM21 and β-catenin in the above mentioned tissues and cell lines. Cell lines with TRIM21 overexpression and knockdown were constructed. CCK-8 method was used to detect the proliferation activity of ovarian cancer cells in each group, TOP/FOP dual luciferase assay was used to detect the effect of TRIM21 on Wnt signaling pathway activation, qPCR and WB were used to detect the effect of TRIM21 on mRNA and protein levels of β-catenin, which was further verified by Wnt pathway inhibitor XAV-939. Results: The expression level of TRIM21 in ovarian cancer tissues was significantly higher than that in cervical epithelial tissues (P<0.01), and its expression was more higher in the drug-resistant tissues (P<0.01). TRIM21 expression was the highest in ES-2 cells but comparatively low in CAOV3 and A270 cells (all P<0.01). After TRIM21 knockdown, the expression of TRIM21 in ES-2 cells was significantly decreased, and the cell proliferation was significantly reduced (all P<0.01). After overexpressing TRIM21, the proliferative capacity of ovarian cancer CAOV3 cells was significantly increased (P<0.01), and the antitumor effect of nilaparib was inhibited; TRIM21 overexpression could regulate Wnt/β -catenin pathway activation, while β -catenin knockdown or Wnt/β -catenin inhibitor XAV-939 could significantly reverse the effect of TRIM21 in ovarian cancer. Conclusion: TRIM21 can enhance the proliferation of ovarian cancer cells via regulating Wnt/β-catenin pathway, it plays a certain role in the process of drug resistance of PARP inhibitor nilapani.