Brain metastasis is common and carries a poor prognosis in melanoma. A single institution, retrospective cohort of 225 melanoma patients was analyzed to determine if BRAF-V600 mutational status was associated with brain metastasis. Eighty-three of the 225 patients (37%) had BRAF-V600 mutations. At initial diagnosis, BRAF-V600 mutations were associated with younger age (p0.001), higher proportion of females (p=0.0037), higher AJCC stage (p=0.030), regional lymph node involvement (p=0.047), and family history of cancer (p=0.044). Compared to BRAF-WT, BRAF-V600 patients had an increased risk of brain metastasis in multivariate analysis (OR=2.24; 95% CL=1.10-4.58; p=0.027). However, BRAF-V600 patients treated with a selective BRAF inhibitor (BRAFi) had a similar risk of brain metastasis compared to BRAF-WT patients (OR=1.00; 95% CL=0.37-2.65; p=0.98). Moreover, treatment with BRAFi significantly prolonged the time from initial diagnosis to brain metastasis diagnosis (HR=0.30; 95% CL=0.11-0.79; p=0.015). Compared to other tissues, the brain was the most frequent site of metastasis in BRAF-V600 patients without BRAFi (42% 7%). The frequency of brain metastasis was lower in BRAF-WT and BRAF-V600 patients with BRAFi (25% 4% and 25% +/- 8%, respectively). The proportion of patients with brain metastasis as the only site was 40%, 60%, and 0% in the BRAF-WT, BRAF-V600 without BRAFi, and BRAF-V600 with BRAFi groups, respectively. This study provides evidence on the clinical importance of BRAF-V600 mutations and BRAF inhibition in the progression to melanoma brain metastasis. What's new? When melanoma spreads to the brain, it usually kills the patient inside a year. How can these metastases be predicted and stopped before they become lethal? These authors investigated whether a mutation in the BRAF gene increases the chances of brain metastasis. From a cohort of 225 melanoma patients, they showed that those carrying a mutation at BRAF-V600 developed brain metastases more often than those with normal copies of the gene. When patients with the BRAF-V600 mutation received treatment with BRAF inhibitor, however, the effect was reversed, and patients experienced the same risk as those without BRAF mutations.