Cisplatin is one of the most frequently used chemotherapeutic agents for the treatment of several human malignancies, and induces caspase-9-mediated apoptosis. Here, we examined whether phospholipase C-related catalytically inactive protein (PRIP) enhances cisplatin-induced apoptosis of cisplatin resistant breast cancer cells. PRIP depletion increased expression of X-linked inhibitor of apoptosis protein (XIAP) by inhibiting protein degradation, which is downstream of PI3K/AKT pathway and inhibits apoptotic signaling by blocking caspase-9 activation. Conversely, XIAP was decreased by expression of PRIP1 or pleckstrin homology domain of PRIP1 (PRIP1-PH domain) that blocked PI(4,5)P₂ metabolism. The expression levels of cleaved caspase-9 and downstream cleaved caspase-7 and poly-ADP ribose polymerase were greater in PRIP1 or PRIP1-PH domain-expressing MCF-7 cells treated with cisplatin than in control cells. In an orthotopic transplantation model, combined administration of PRIP1-PH domain-containing liposomes and cisplatin reduced the size of MCF-7 tumors compared with cisplatin alone. Our findings demonstrate that PRIP promotes XIAP degradation by inhibiting PI(3,4,5)P₃/AKT signaling and enhances cisplatin-induced apoptotic cell death. Therefore, we propose that PRIP1-PH-liposomes are a novel agent to avoid cisplatin resistance.