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 (p ≤ 0.001), 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.