Background: Emerging data suggest that RAF inhibitors are an effective therapy for pts with BRAF-mutant melanoma and brain mets. Although reported efficacy is encouraging, these data are derived from case reports or early stage trials enriched with physiologically fit pts. It is therefore of interest to assess the “real world” experience of VEM in this population. Methods: Records of all BRAF-mutant melanoma pts treated with RAF inhibitors at our center from 2007 to 2012 were reviewed retrospectively. We determined the best overall response rate (BORR) and, when applicable, the overrall intracranial response rate (OIRR) by RECIST v1.1, progression-free survival (PFS), and overall survival (OS) to RAF inhibition. Pretreatment formalin-fixed, paraffin-embedded tumor was assessed using an exon capture assay able to sequence coding exons of 279 cancer-associated genes. Results: 21 (18%) of 119 pts with BRAF-mutant melanoma treated with VEM had active brain mets (age range: 25-86, sex: 52% men, median ECOG PS: 1, proportion with extracranial mets: 90%, BRAF mutation: 86% V600E and 14% V600K). 10/21 pts had no prior intracranial (IC) therapy; 11/21 pts received whole brain radiotherapy (WBRT, 7/21), stereotactic radiosurgery (1/21), metastasectomy (2/21) or multimodality therapy (1/21) prior to VEM. 12/21 pts received ipilimumab sometime during their disease course. For radiographically evaluable pts (N=17), the BORR was 65% (95% CI: 43-88) and the OIRR was 40% (95% CI: 15-65). For 4 pts, the BORR and OIRR were discordant−3 pts had IC progression but visceral tumor shrinkage, 1 pt had IC disease control but visceral progression. VEM was effective in pts whether or not they had received prior local brain therapy. The estimated median PFS and OS for all brain mets pts (N=21) were 4 and 8 months, respectively. Pretreatment tumor is available for exon sequencing in approximately half of these patients. This analysis is ongoing. Conclusions: In routine clinical practice, the OIRR to VEM was 40% which is higher than historical response rates to WBRT. VEM may be preferable to WBRT as a first-line therapy for pts with BRAF-mutant melanoma and brain mets. Whether RAF inhibitor treatment improves OS in this population will require further study.