Growth and dissemination of malignant melanoma has a profound impact on our population, and little is known concerning the mechanisms controlling this disease in humans. Evidence is provided that integrin α_Vβ₃ plays a critical role in M21 melanoma tumor survival within human skin by a mechanism independent of its known role in angiogenesis. Antagonists of α_Vβ₃ blocked melanoma growth by inducing tumor apoptosis. Moreover, M21 melanoma cell interactions with denatured collagen, a known ligand for α_Vβ₃, caused a 5-fold increase in the relative Bcl-2:Bax ratio, an event thought to promote cell survival. Importantly, denatured collagen colocalized with α_Vβ₃-expressing melanoma cells in human tumor biopsies, suggesting that α_Vβ₃ interaction with denatured collagen may play a critical role in melanoma tumor survival in vivo.