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We detected low <jats:italic>PRRX1<\/jats:italic> expression in nevus but increased levels in primary human melanoma and cell lines carrying the <jats:italic>BRAF<\/jats:italic><jats:sup><jats:italic>V600E<\/jats:italic><\/jats:sup> mutation. High expression of <jats:italic>PRRX1<\/jats:italic> correlates with invasiveness and enrichment of genes belonging to the EMT programme. Conversely, we found that loss of <jats:italic>PRRX1<\/jats:italic> in metastatic samples is an independent prognostic predictor of poor survival for melanoma patients. Here, we show that stable depletion of PRRX1 improves the growth of melanoma xenografts and increases the number of distant spontaneous metastases, compared to controls. We provide evidence that loss of <jats:italic>PRRX1<\/jats:italic> counteracts the EMT phenotype, impairing the expression of other EMT\u2010related transcription factors, causing dysregulation of the ERK and signal transducer and activator of transcription 3 (STAT3) signaling pathways, and abrogating the invasive and migratory properties of melanoma cells while triggering the up\u2010regulation of proliferative\/melanocytic genes and the expression of the neural\u2010crest\u2010like markers nerve growth factor receptor (NGFR; also known as neurotrophin receptor p75NTR) and neural cell adhesion molecule L1 (L1CAM). 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