Paclitaxel-containing treatment regimens are standard chemotherapy schemes for breast cancer patients. The use of oncolytic herpes simplex virus (oHSV) vectors has been shown to be a safe and effective therapeutic approach for different types of cancer. We hypothesized that paclitaxel in combination with an oHSV vector would present an enhanced killing effect when used against breast cancer cells. In the present study, we demonstrated that the combined use of the oHSV vector G47 Delta and paclitaxel produced a synergistic effect against breast cancer cells both in vitro and in vivo. In vitro studies demonstrated that paclitaxel and G47 Delta both caused dose-dependent cytotoxicity against the human breast cancer cell lines MCF-7 and MDA-MB-468. G47 Delta and paclitaxel also demonstrated synergistic cytotoxicity when applied together, with Chou-Talalay combination indices ranging from 0.44 to 0.77 for MCF-7 cells and 0.68 to 0.83 for MDA-MB-468 cells. Paclitaxel did not enhance viral replication or viral spread among tumor cells. However, G47 Delta increased the antitumor ability of paclitaxel by inducing mitotic arrest and apoptosis. In vivo studies indicated that when combined with G47 Delta, the dose of paclitaxel could be reduced at least 5-fold while maintaining levels of tumor reduction similar to those achieved with the administration of paclitaxel alone. Combination therapy resulted in no morbidity in vivo. Our data demonstrated that G47 Delta and paclitaxel combination therapy had synergistic effects in the treatment of breast cancer. This combination therapy may be promising for breast cancer patients.