Tamoxifen (Tam), a selective estrogen receptor modulator, is in wide clinical use for the treatment and prevention of breast cancer. However, extended TAM administration for breast cancer induces increased VEGF levels in patients, promoting new blood vessel formation and thereby limiting its efficacy and highlighting the need for improved therapeutic strategies. Cyclooxygenase-2 (COX-2) silencing via a replication-incompetent lentivirus (LV-COX-2) induce cancer apoptosis and suppresses VEGF gene expression. In this study, the effect of LV-COX-2 infection, either alone or in combination with TAM, was analyzed in a breast cell lines for suppressing VEGF expression and simultaneously reducing doses of TAM. Cell proliferation, apoptosis, angiogenesis, metastasis, cell cycle distribution, an receptor signaling were determined after LV-COX-2 combination with TAM treatment. In addition, tumor growth ability in nude mice was detected to define the combination treatment effect in tumorigenesis in vivo. It is found that LV-COX-2 combination with TAM treatment in breast cancer cell significantly suppressed the proliferation and metastasis, and induced tumor apoptosis in vitro, and tumor growth also was suppressed in vivo. In addition, we also found that LV-COX-2 combination with TAM treatment could inhibit angiogenesis and VEGF expression. Taken together, our experimental results indicate that LV-COX-2 combination with TAM has promising outcome in anti-metastatic and apoptotic studies. Furthermore, these results showed that LV-COX-2 combination with TAM is a potential drug candidate for treatment of breast tumors expressing high levels of VEGF.