Tumor metastasis represents a complex multistep process that requires migration, invasion, and angiogenesis. In this study, we examined the impact of molecular blockade of the epidermal growth factor receptor on the invasive and metastatic capacity of human squamous cell carcinoma (SCC) of the head and neck using in vitro and in vivo model systems. Treatment with the anti-epidermal growth factor receptor antibody C225 attenuated the migration of SCC-1 tumor cells through a chemotaxis chamber in a dose-dependent manner. Incubation of SCC cells with 10–100 nm C225 for 4 h resulted in 40–60% inhibition of cell migration. Furthermore, in the presence of C225, the capacity of SCC-1 to invade across a layer of extracellular matrix (Matrigel) was significantly inhibited. Using an in vivo orthotopic floor-of-mouth xenograft model, locoregional tumor invasion of SCC-1 into muscle, vessel, bone, and perineural tissues was inhibited in C225-treated mice. This inhibition was additionally characterized by down-regulation in the expression of matrix metalloproteinase-9. These data suggest that inhibition of metastatic potential by C225 may be mediated via decreased migration and invasion of SCC cells. Regarding angiogenesis in vitro, we first studied human umbilical vascular endothelial cells, which established a capillary-like network structure (tube formation) in the presence of reconstituted Matrigel. Treatment with C225 reduced cell-to-cell interaction of human umbilical vascular endothelial cells, resulting in disruption of tube formation. The effect of C225 was additionally examined using an in vivo tumor xenograft neovascularization model of angiogenesis. Systemic treatment with C225 not only reduced tumor growth and the number of blood capillaries but also hindered the growth of established vessels toward the tumor. Taken together, these results provide evidence that C225 can suppress tumor-induced neovascularization and metastasis in SCC of the head and neck.