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We found ganglioside GD3 levels significantly upregulated in MBM compared to lymph node metastasis (LNM) but not for other melanoma gangliosides. Moreover, we demonstrated an upregulation of ST8SIA1 (GD3 synthase) as melanoma progresses from melanocytes to MBM cells. Using RNA\u2010ISH on FFPE specimens, we evaluated ST8SIA1 expression in primary melanomas (PRM) (<jats:italic>n<\/jats:italic>\u00a0=\u00a023), LNM and visceral metastasis (<jats:italic>n<\/jats:italic>\u00a0=\u00a045), and MBM (<jats:italic>n<\/jats:italic>\u00a0=\u00a039). ST8SIA1 was significantly enhanced in MBM compared to all other specimens. ST8SIA1 expression was assessed in clinically well\u2010annotated melanoma patients from multicenters with AJCC stage III B\u2010D LNM (<jats:italic>n<\/jats:italic>\u00a0=\u00a058) with 14\u2010year follow\u2010up. High ST8SIA1 expression was significantly associated with poor overall survival (HR\u00a0=\u00a03.24; 95% CI, 1.19\u20138.86, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.02). In a nude mouse human xenograft melanoma brain metastasis model, MBM variants had higher ST8SIA1 expression than their respective cutaneous melanoma variants. Elevated ST8SIA1 expression enhances levels of cell surface GD3, a phenotype that favors MBM development, hence associated with very poor prognosis. Functional assays demonstrated that ST8SIA1 overexpression enhanced cell proliferation and colony formation, whereby ST8SIA1 knockdown had opposite effects. Icaritin a plant\u2010derived phytoestrogen treatment significantly inhibited cell growth in high GD3\u2010positive MBM cells through targeting the canonical NF\u03baB pathway. 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