Overexpression of HER-2 accounts for approximately 25% of all breast cancer cases, while 87.7% of HER-2 positive breast cancers are associated with upregulated VEGF. The objective of this study is to explore the combination therapy of blocking HER-2 and VEGF expressions simultaneously using siRNA. This is the first report to examine the effect of dual silencing of HER-2 and VEGF genes on tumor growth and invasiveness. We have designed nine HER-2 siRNAs and ten VEGF siRNAs, and identified potent siRNA which can silence the target gene up to 75-83.5%. The most potent HER-2 and VEGF siRNAs were used to conduct functional studies in HER-2 positive breast cancer cells. Tumor invasiveness properties including cell morphology change, in vitro migration, cell spreading, and adhesion to ECM were evaluated. In addition, cell proliferation and apoptosis were examined after the siRNA treatment. Our data demonstrated for the first time that HER-2 siRNA could inhibit cell migration and invasion abilities. Combination of HER-2 and VEGF siRNAs exhibited synergistic silencing effect on VEGF. Both HER-2 siRNA and VEGF siRNA showed significant inhibition on cell migration and proliferation. HER-2 siRNA also demonstrated dramatic suppression on cell spreading and adhesion to ECM, as well as induction of apoptosis. Dual silencing of HER-2 and VEGF exhibited significant cell morphology change, and substantial suppression on migration, spreading, cell adhesion, and proliferation. Our observations suggested that HER-2 positive breast cancer may be more effectively treated by dual inhibition of HER-2 and VEGF gene expressions using siRNA.