The plasma exosome-derived SENP1 levels in melanoma patients with tumor size >10 cm, located in the mucosa or viscera, with Clark level IV/V, lymph node metastasis, and TNM stages IIb–IV were significantly higher than in patients in with tumor size <10 cm, located in the skin, with Clark level I–III, without lymph node metastasis, and TNM stages IIb–IV. This evidence concerns the gene SENP1 and melanoma.