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The most frequently reported skin tumours during treatment with targeted therapies for BRAF (B type Rapidly Accelerated Fibrosarcoma kinase) mutated metastatic melanoma are squamous cell carcinomas (SCCs). Basal cell carcinomas (BCCs) have been described in such setting, but no cases of multiple and recurring tumours have been reported so far. A patient with a history of chronic sun exposure and more than 10 BCCs removed since 1998 started treatment with vemurafenib for BRAF mutated metastatic melanoma. Therapy was complicated by sporadic episodes of atrial fibrillation and by the development of recurrent, multiple and diffuse BCCs. So, vemurafenib was discontinued and dabrafenib and trametinib were started. Since then, only four BCCs occurred in the patient. Histopathological re-examination showed that most BCCs occurred under vemurafenib presented with squamous features. Such characteristic was significantly less evident before therapy start and in lesions removed under treatment with dabrafenib and trametinib. BRAF inhibition (BRAFi) without MEK inhibition induces mitogen activated kinases overactivation, with consequent skin toxicity and acquired drug resistance. The BCCs removed from our patient showed squamous features, more evident during vemurafenib monotherapy. Both the switch from vemurafenib to dabrafenib and the addition of MEK inhibitor (MEKi) might have reduced the incidence of BCCs and their squamous differentiation.