Melanoma cells facilitate endothelial gap formation, the first step during tumor transendothelial migration, which is mediated by both adhesion and endogenously produced chemokines (in particular, interleukin-8 (IL-8)). Tetraspanins are localized to the cell surface in cancer and participate in various functions including invasion of tissues mediated by secretion of cytokines and matrix metalloproteinases. However, little is known about the role of CD82 tetraspanins in malignant melanomas during cancer cell invasion. In this study, we investigated the functional importance of CD82 expression in melanoma-mediated gap formation by using cDNAs to induce CD82 expression in highly invasive melanoma cell lines. Results showed that CD82 expression inhibited melanoma cell-induced gap formation, melanoma cell extravasation in vitro and subsequent lung metastasis development in vivo. Mechanistic studies showed that inducible expression of CD82 in highly metastatic melanoma cells significantly increased p21 expression upon binding of Duffy antigen receptor group (DARC), inducing tumor cell senescence and interrupting IL-8-mediated vascular endothelial (VE)-cadherin disassembly. Taken together, these studies provide a rationale for using drug therapies that restore CD82 expression and inhibit IL-8 production to inhibit late-stage melanoma cell extravasation and subsequent metastasis development.