PARP inhibitors (PARPi) are efficacious in treating high-grade serous ovarian cancer (HG-SOC) with homologous recombination (HR) deficiency. However, they exhibit suboptimal efficiency in HR-proficient cancers. Here, we found that the expression of CCAAT/enhancer-binding protein beta (C/EBP beta), a transcription factor, was inversely correlated with PARPi sensitivity in vitro and in vivo, both in HR-proficient condition. High C/EBP beta expression enhanced PARPi tolerance; PARPi treatment in turn induced C/EBP beta expression. C/EBP beta directly targeted and upregulated multiple HR genes (BRCA1, BRIP1, BRIT1, and RAD51), thereby inducing restoration of HR capacity and mediating acquired PARPi resistance. C/EBP beta is a key regulator of the HR pathway and an indicator of PARPi responsiveness. Targeting C/EBP beta could induce HR deficiency and rescue PARPi sensitivity accordingly. Our findings indicate that HR-proficient patients may benefit from PARPi via targeting C/EBP beta, and C/EBP beta expression levels enable predicting and tracking PARPi responsiveness during treatment.