Cutaneous melanoma is the most aggressive skin cancer; it is highly metastatic and responds poorly to current therapies. Platelet Derived Growth Factor Receptors (PDGF-Rs) expression is reported to be reduced in metastatic melanoma, compared to benign nevi or normal skin; we then hypothesized that PDGF-Ralpha may control melanoma cells growth. We show here that melanoma cells over-expressing PDGF-Ralpha respond to serum with a significantly lower proliferation as compared to controls. Apoptosis, cell cycle arrest, pRb de-phosphorylation and DNA synthesis-inhibition were also observed in cells over-expressing PDGF-Ralpha. Proliferation was rescued by PDGF-Ralpha inhibitors, allowing to exclude non-specific toxic effects and indicating that PDGF-Ralpha mediates autocrine anti-proliferation signals in melanoma cells. Accordingly, PDGF-Ralpha was found to mediate staurosporine cytotoxicity. A protein array-based analysis of the MAP-kinase pathway revealed that melanoma cells over-expressing PDGF-Ralpha show strong reduction of c-Jun phosphorylated in serine 63 and of PP2A/Balpha phosphatase, and marked increase of p38 gamma, MKK3 and SIRPalpha1 protein expression. In a mouse model of primary melanoma growth, infection with the Ad-vector over-expressing PDGF-Ralpha reached a significant 70% inhibition of primary melanoma growth (p<0.001) and a similar inhibition of tumor-angiogenesis. All together these data demonstrate that PDGF-Ralpha strongly impairs melanoma growth likely via autocrine mechanisms and indicate a novel endogenous mechanism involved in melanoma control.