Brain metastases (brain mets) are frequent in metastatic melanoma patients. The aim of this study was to investigate the morphology and progression pattern of brain mets in melanoma patients treated with BRAF inhibitors (BRAFi) compared with patients who did not receive targeted therapy (BRAFi group and control group). The number and size of brain mets were compared between a baseline and a comparative MRI at progression. The number of brain mets was grouped into seven number classes (N=1–4, N=5–10, N=11–20, N=21–30, N=31–40, N=41–50, and N>50) and its difference was reported as the change of class that occurred. The mean size of the newly developed lesions was determined by representative measurements and the evolution of three persisting target lesions was assessed on the basis of modified RECIST criteria. Of 96 patients studied, 42 were in the BRAFi group and 54 were in the control group. Patients under BRAFi treatment had a significantly greater increase in the number of brain mets, where the median change of class for the BRAFi compared with the control group was 2 versus 0 (P<0.01). The mean size of the new lesions was smaller in the BRAFi group. Pre-existing target lesions did not show any prominent or different patterns of how they evolved in either group. Brain mets in patients treated with BRAFi showed a progression pattern characterized by a high propensity to disseminate, which might reflect an in-vivo manifestation of phenotype switching in response to targeted therapy, with a predominance of the invasive/migratory tumor cell phenotype. Drivers of invasiveness may present promising targets for therapeutic interventions.