Background: Nearly 50% of metastatic melanoma patients develop brain metastases, warranting further investigation into the biology of this event. Methods: We analyzed 132 MBM and 745 CM submitted to Caris Life Sciences from 2015-2018, using next generation sequencing of a 44 or 592 cancer-related gene panel, tumor mutational burden (TMB), and PD-L1 expression by IHC. Genomic alterations (GA), including somatic mutations or CNA, were reported. High TMB (TMB-H) was defined as ≥17 mut/Mb. Comparison of molecular profiles, including cancer-related genes and recurrently altered pathways, between tumor sites and by genomic subgroup (BRAF, NRAS, KIT, NF1), was performed using Fisher’s exact test. Results: Among 132 MBM, 72.7% were male, with median age 62 yo (range 25-83). The most common GAs among MBM were: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Compared to CM, MBM were more often TMB-H (53.7% v 38%, p = .025), with higher PD-L1 expression, using both a ≥1% (54.4% v 35.6%, p = .002) and ≥5% cut-off (32.9% v 15.9%, p = .0006). MBM showed higher rates of GAs among: SETD2 (11.9% v 1.9%, p = .0008), BRAF (52.4% v 35.6%, p = .017), PBRM1 (7.5% v 1.6%, p = .018), KRAS (4% v 1%, p = .026), CCND1 (2.9% v 0%, p = .03), and DICER1 (4.4% v 0.6%, p = .04), compared to CM. Alterations of the MAPK (87.9% v 77.8%, p = .015) and SWI/SNF (22.1% v 11.6%, p = .036) pathway were more frequent in MBM, than CM. When analyzed by genomic subgroup, BRAF+ MBM had more GAs involving the PI3K pathway (20% v 5.1%, p = .027), compared to BRAF WT MBM. NRAS+ MBM had higher PD-L1 expression at the ≥1% cutoff (66.7% v 38.6%, p = .05), but not ≥5%, compared to NRAS WT MBM. NF1+ MBM had more GAs involving the SWI/SNF (60% v 11.6%, p = .003) pathway, as opposed to NF1 WT MBM. No significant associations were seen between KIT status, TMB, PD-L1 or other pathways among MBM. Conclusions: In this cross-sectional study, MBM demonstrated higher PD-L1 expression and were more often TMB-H, compared to CM. MBM also featured more GAs involving BRAF and the MAPK pathway. We identified two novel genes, PBRM1 and SETD2, as well as recurrent alterations of the SWI/SNF pathway, supporting future studies of chromatin remodeling pathways in MBM.