Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been recognized as a promising target for cancer therapy because it can induce apoptotic cell death in tumor cells but not normal cells. Although TRAIL shows specific tumoricidal activity, resistance to TRAIL-induced apoptosis in some tumor cells has been considered a clinical obstacle of its application. It has been shown that TRAIL provides inflammatory signals that may contribute to the TRAIL-resistance of cancer cells; however, it is not known whether TRAIL itself is involved in malignant cancer cell behavior. In the present study, we examined the functional role of TRAIL in B16F10 mouse melanoma cells, which are totally insensitive to TRAIL-induced apoptosis. By establishing B16F10 cells stably expressing the nuclear factor-κB (NFκB)-luciferase reporter gene, we found that TRAIL can activate NFκB through its death receptor DR5 in B16F10 cells. Furthermore, TRAIL–DR5 interaction not only promoted malignant behaviors of B16F10 cells, such as cell proliferation and MMP-9 production, but also induced lung metastasis of B16F10 cells in vivo. These findings may imply a contrary role for the TRAIL–DR5 pathway in the inflammatory tumor microenvironment, in its ability to induce the metastatic potential of B16F10 melanoma cells instead of inducing apoptosis.