Melanoma cells that expressed GFP-Interferon stimulated gene 15 (ISG15) or GFP-Interferon-induced protein with tetraticopeptide repeats 3 (IFIT3) fusion reporters exhibited a profoundly increased ability to form metastatic tumors as compared to GFP-ISG15<sup>-</sup> melanoma cells from the same tumors, particularly when transplanted into immunocompetent mice. This evidence concerns the gene ISG15 and melanoma.