The morphogenetic properties of endothelial cells and melanoma cells were tested under varying matrix quantities and distributions and under constant and saturating levels of growth factors. Aggressive melanoma cells self-assembled into cords vasculogenically only when seeded on thin matrices: nonaggressive melanoma cells did not mimic endothelial cell behavior under any matrix thickness. When buried in matrix, however, aggressive melanoma cells generated looping patterns that contained tumor cells and matrix. These patterns were different topologically and compositionally from cord-like structures or blood vessels but were nevertheless capable of conducting dye by microinjection or passive diffusion. When seeded on three-dimensional cultures of nonaggressive nonpattern-forming melanoma cells, prelabeled endothelial cells attached to, penetrated through, and survived for 2 weeks but failed to form vasculogenic cords. In cocultures containing aggressive melanoma cells, endothelial cells survived briefly but formed short cords only in contact with looping patterns formed by the aggressive tumor cells. Time-lapse recording showed that endothelial cells were lysed upon direct contact with aggressive melanoma cells. Looping patterns identified in human tissue samples were composed ultrastructurally of electron-dense material on either side of a layer of tumor cells; scattered red blood cells were seen in this central cellular layer. By immunohistochemistry, patterns labeled with laminin and fibrinogen colocalized to these looping laminin-positive patterns, suggesting the presence of plasma within these patterns from contiguous leaky tumor vessels. These observations are consistent with the perfusion of these patterns in vitro and with repeated demonstrations of the colocalization of intravenous tracers to looping laminin patterns in animal xenograft models by independent groups. Thus, the distribution and localized quantity of extracellular matrix in aggressive melanomas contributes to the regulation of tumor cell morphogenesis, modulates interactions between tumor cells and endothelial cells, and may contribute to an extravascular matrix-directed circulation.