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Xiangyu Zhang, 1,* Jingwen Huang, 2,* Chao Yu, 3 Longquan Xiang, 1 Liang Li, 1 Dongmei Shi, 4 Fanzhong Lin 1 1Department of Pathology, Jining First People’s Hospital, Jining Medical University, Jining 272000, People’s Republic of China; 2Anhui Province Key Laboratory of Translational Cancer Research Affiliated to Bengbu Medical University, Bengbu 233004, People’s Republic of China; 3Department of Clinical Medicine, Jining Medical University, Jining 272000, People’s Republic of China; 4Department of Dermatology, Jining First People’s Hospital, Jining Medical University, Jining 272000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongmei ShiDepartment of Dermatology, Jining First People’s Hospital, Jining Medical University, No. 6 Jiankang Road, Jining 272000, People’s Republic of ChinaTel/Fax +86 537 6051547Email shidongmei28@163.comFanzhong LinDepartment of Pathology, Jining First People’s Hospital, Jining Medical University, No. 6 Jiankang Road, Jining 272000, People’s Republic of ChinaTel/Fax +86 537 6051547Email linfanzhong1@126.comIntroduction: Prostate cancer is one of the most common cancers threatening public health worldwide. Although chemotherapy plays an important role in treating prostate cancer, it leads to many adverse effects and is prone to drug resistance. Quercetin, a natural product, is used in traditional Chinese medicine because of its strong antitumor activity and few side effects.Methods: In this study, we combined quercetin and paclitaxel to kill prostate cancer cells in vivo and in vitro, and we investigated the relevant mechanism of this combination treatment. After the cancer cells were treated with quercetin or/and paclitaxel, cell growth inhibition, apoptosis, the cell cycle, reactive oxygen species (ROS) generation, and several endoplasmic reticulum (ER) stress signaling pathway related gene expressions were evaluated.Results: The combined treatment with quercetin and paclitaxel significantly inhibited cell proliferation, increased apoptosis, arrested the cell cycle at the G2/M phase, inhibited cell migration, dramatically induced ER stress to occur, and increased ROS generation. In a PC-3 cancer-bearing murine model, this combination treatment exerted the most beneficial therapeutic effects, and quercetin increased the cancer cell-killing effects of paclitaxel, with nearly no side effects compared with the single paclitaxel treatment group.Conclusion: Combination treatment possessed enhanced anti-cancer effects, and these results will provide a basis for treating prostate cancer using a combination of quercetin and paclitaxel.Keywords: quercetin, paclitaxel, combination treatment, endoplasmic reticulum stress, reactive oxygen species