Vasculogenic mimicry (VM) is a tumor angiogenesis process in which highly aggressive melanoma cells form patterned, tubular networks in an in vitro, three-dimensional culture that mimics vasculogenic networks formed by endothelial cells. These cells also express endothelial cell-associated genes such as vascular endothelial-cadherin (VE-cadherin) and are correlated with poor clinical prognosis in patients. However, the molecular underpinnings of this phenomenon remain elusive. Three-dimensional cultures of highly and poorly aggressive uveal melanoma cells were observed by inverted light microscope and scanning electronic microscope for VM. RNAi (RNA interference) technology was used to examine whether inhibitor of DNA binding 2 (Id2) was involved in the uveal melanoma vasculogenic mimicry. Western blot analysis showed changes of Id2 and VE-cadherin expression in highly and poorly aggressive melanoma cells in vitro. Migration analysis of highly and poorly aggressive uveal melanoma cells in vitro illuminated the role of Id2 in tumor cells migration. We show here that a transient knockdown of Id2 by RNA interference abrogates VM and VE-cadherin expression in highly aggressive uveal melanoma cells. Furthermore, inhibition of Id2 changes cellular stability and creates a more dynamic condition. Transfected cells also migrate better than untransfected cells. This study shows that Id2 is an important regulator of VM. Specifically, Id2 affects VE-cadherin expression, and is critical for the formation of vasculogenic-like networks.