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We characterized NK cells from peripheral blood <jats:italic>ex vivo<\/jats:italic> by flow cytometry obtained from late stage (III\/IV) melanoma patients. Interestingly, we found that the abundance of CD56<jats:sup>bright<\/jats:sup> NK cells negatively correlate with overall patient survival, together with distant metastases, in a multivariate cox regression analysis. The patients\u2019 CD56<jats:sup>bright<\/jats:sup> NK cells showed upregulation of CD11a, CD38 and CD95 as compared to healthy controls, pointing to an activated phenotype as well as a possible immune regulatory role in melanoma patients. After stimulation <jats:italic>in vitro<\/jats:italic>, CD56<jats:sup>bright<\/jats:sup> NK cells produced less TNF\u03b1 and GMCSF in patients than controls. Furthermore, IFN\u03b3 production by the CD56<jats:sup>bright<\/jats:sup> NK cells correlated inversely with overall survival. 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