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Prostate cancer is a major public health problem among elderly men. In the United States, it is the second leading cause of cancer-related death among men. We investigated the therapeutic potential of combining siRNA-based medicine and ABT-263 in a prostate cancer mouse model (an orthotopic PC-3 transplanted nude mouse model). Both medicines target an anti-apoptotic protein, Bcl-xL. To deliver the siRNA-based medicine, we used a biomaterial atelocollagen as a delivery vehicle specific to tumors. Atelocollagen shows great advantages as a carrier for siRNA systemic delivery. We previously reported that an siRNA targeting human Bcl-xL showed that atelocollagen-mediated systemic delivery of the siRNA significantly suppressed tumor progression in a PC-3 orthotopic tumor model. Thus, we decided to investigate whether the therapeutic potential of the Bcl-xL siRNA complexed with atelocollagen could be increased by further inhibiting Bcl-xL by ABT-263. The intravenous injection of Bcl-xL siRNA mixed with atelocollagen (50 mg siRNA/shot) plus oral administration of ABT-263 (50 mg/kg) significantly and synergistically inhibited tumor growth in the PC-3 orthotopic model compared with each single administration. A luciferase-expressing PC-3 cell line was used to evaluate liver metastasis. The combined treatment of the siRNA and ABT-263 almost completely inhibited liver metastasis. The combined administration of Bcl-xL siRNA and ABT-263 indicated a synergistic therapeutic effect, suggesting that our proposed therapy has excellent potential to treat prostate cancers.