Background: In the pigmentation of hair and skin a key role is played by the MC1R gene whose inherited variations are linked with a higher melanoma risk. In melanoma cells, MC1R has a central role because of its interaction with several intracellular signaling cascades such as the MAPK or mTOR pathways. Little heed has been paid to the role of its genetic polymorphisms in the management of metastatic melanoma. Our aim was to evaluate the effects of MC1R variants on the clinical outcomes of BRAF mutated patients treated with BRAF inhibitors. Methods: Fifty-three consecutive patients were evaluated according to their MC1R status (21 wild type and 32 with minor/major functional variants). First we explored eventual association between MC1R status and basal patient features. Than we evaluated the influence of MC1R status on therapeutic outcomes to anti BRAF inhibitors (ORR, PFS, OS). Finally, we studied the effect of vemurafenib in 2 BRAF V600 melanoma cell lines with and without MC1R variant. Results: Regarding the baseline patient features, we only found an association between MC1R polymorphisms and bone metastases (p 0.017). Moreover, MC1R variants were significantly associated with worse outcomes to BRAF inhibitors compared with MC1R wild type in terms of both ORR (59% vs 95% [p 0.011 in univariate, p 0.028 in multivariate analysis]) and PFS shorter than 6 months (72% vs 33% [p 0.012 in univariate, p 0.027 in multivariate analysis]). No significant difference was found in OS, probably due to the influence of further treatments. Data in vitro demonstrated a significantly different phosphorylation of Erk1/2 and p38 MAPK before and after treatment, associated with a greater increase of vemurafenib IC50 in cases of MC1R variant. Conclusions: Our data document, for the first time, detrimental effects of MC1R variants on BRAF inhibitor therapy. Moreover, these evidences concur to understand the resistance mechanisms to targeted therapy and may help to pinpoint new therapeutic strategies.