Background and Purpose: Mutations in the Breast cancer (BRCA) gene have been associated with a heightened risk of breast, ovarian, and various other types of cancer. Poly (ADP-ribose) polymerase (PARP) inhibitors induce synthetic lethality in cancer cells that exhibit BRCA mutations. The focus of this study is to elucidate the connection between phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit a (PIK3CA), p35 gene polymorphism and the prognosis of breast cancer patients following treatment with PARP inhibitors. Methods: Between February 2015 and April 2018, 158 breast cancer (BC) patients were enrolled in this study. We compared the polymorphisms of the PIK3CA and p35 genes in cancerous tissue and adjacent non-cancerous tissue, assessed the mRNA and protein expressions of PIK3CA and p35, and evaluated their diagnostic significance for BC. All patients received treatment with PARP inhibitors. Furthermore, we analyzed the correlation between PIK3CA and p35 gene polymorphisms and the clinical efficacy of the treatment. Patients were categorized into two cohorts according to their survival status three years after treatment: survival and the death groups. Subsequently, we examined the relationship between the polymorphisms of the PIK3CA and p35 genes and the patients prognoses. Results: PIK3CA gene mutations and p35 gene CG/GG variants in cancer tissues were significantly higher than in adjacent tissues (p < 0.05). The simultaneous detection of PIK3CA and p35 expressions proved to have a larger Area Under the Curve (AUC), thus enhancing diagnostic accuracy for breast cancer, compared to individual detection (p < 0.05). A higher detection rate was observed for PIK3CA mutations and p35 CG/GG variants in non-remission cases versus those in remission (p < 0.05). Evaluating the effectiveness of PARP inhibitors via combined detection of PIK3CA and p35 expressions provided an increased AUC compared to the individual analysis (p < 0.05). The mortality and recurrence rates for PIK3CA gene mutations were significantly higher than the wild type (p < 0.05). However, no notable difference was found when comparing the mortality, recurrence rate, and distant metastasis rate of the p35 gene in both wild and mutated types (p < 0.05). Conclusions: The combined detection of PIK3CA and p35 expressions in BC tissues offers valuable diagnostic insight for BC and is an effective measure to evaluate the therapeutic efficacy of PARP inhibitors. Additionally, polymorphisms of the PIK3CA gene are associated with the prognosis of patients receiving PARP inhibitor treatment.