The US Food and Drug Administration (FDA) approved vemurafenib to treat patients with metastatic melanoma harboring the BRAF c.1799T>A (p.V600E) mutation. However, a subset of melanomas harbor non-p.V600E BRAF mutations, and these data are of potential importance regarding the efficacy of current targeted therapies. To better understand the BRAF mutation profile in melanomas, we retrospectively analyzed data from 1112 primary and metastatic melanomas at our institution. The cohort included nonacral cutaneous (n = 774), acral (n = 111), mucosal (n = 26), uveal (n = 23), leptomeningeal (n = 1), and metastatic melanomas of unknown primary site (n = 177). BRAF mutation hotspot regions in exons 11 and 15 were analyzed by pyrosequencing or with the primer extension MassARRAY system. A total of 499 (44.9%) specimens exhibited BRAF mutations, involving exon 15 [497 (99.6%)] or exon 11 [2 (0.4%)]. p.V600E was detected in 376 (75.4%) cases; the remaining 123 (24.6%) cases exhibited non-p.V600E mutations, of which p.V600K was most frequent [86 (17.2%)]. BRAF mutations were more frequent in nonacral cutaneous (51.4%) than acral melanomas [18 (16.2%)] (P < 0.001); however, there was no significant difference among cutaneous histological subtypes. All mucosal, uveal, and leptomeningeal melanomas were BRAF wild type (WT). The high frequency of non-p.V600E BRAF mutations in melanoma has important implications because the FDA-approved companion diagnostic test for p.V600E detects some but not all non-p.V600E mutations. However, the therapeutic efficacy of vemurafenib is not well established in these lesions.