The purpose of this study was to determine the role of nuclear factor(NF)-κB/relA activity in the induction of angiogenesis and production of metastasis by human melanoma cells. Highly metastatic melanoma variant cells expressed high levels of constitutive NF-κB activity. Transfection of highly metastatic human melanoma variant cells with a dominant-negative mutant inhibitor of nuclear factor-κBα(Iκβα) expression vector (IκβαM) decreased the level of constitutive NF-κB activity, inhibited s.c. tumor growth, and prevented lung metastasis in nude mice. Furthermore, the slow-growing s.c. tumors formed by the IκBαM-transfected cells exhibited a decrease in microvessel density (angiogenesis), which correlated with a decrease in the level of interleukin-8 expression. Collectively, these results demonstrate that NF-κB/relA activity significantly contributes to tumorigenicity, angiogenesis, and metastasis of human melanoma cells implanted in nude mice.