Administration of tumor necrosis factor (TNF) and γ interferon (IFN-γ) to melanoma patients causes selective disruption of the tumor vascuiature but the mechanism of this disruption is unknown. Here we report that exposure of human endotheliai cells to TNF and IFN-γ results in a reduced activation of integrin αVβ3, an adhesion receptor that plays a key role in tumor angiogenesis, leading to a decreased αVβ3-dependent endotheliai cell adhesion and survival. Detachment and apoptosis of angiogenic endotheliai cells was demonstrated in vivo in melanoma metastases of patients treated with TNF and IFN-γ. These results implicate integrin αVβ3 in the anti-vascular activity of TNF and IFN-γ and demonstrate a new mechanism by which cytokines control cell adhesion.