No specific biomarkers for prognostication or evaluation of tumour load in melanoma have been reported to our knowledge. MicroRNAs (miRNAs) are strongly implicated in oncogenesis and tumour progression, and their circulating forms have been studied as potential biomarkers in oncology. The aim of this prospective study was to identify a melanoma-specific profile of plasma miRNAs. A screening phase, using RNA microarray, was conducted on plasma from 14 patients with metastatic melanoma and 5 healthy subjects. Selected miRNAs were analysed by RTqPCR in 2 independent training and validation cohorts including, respectively, 29 and 31 patients and 16 and 43 control subjects. A profile of 2 miRNAs (miR-1246 and miR-185) significantly associated with metastatic melanoma with a sensitivity of 90.5% and a specificity of 89.1% was identified. This plasma miRNA profile may become an accurate non-invasive biomarker for melanoma.