Objectives: Vulvar and vaginal melanomas are rare cancers that are biologically aggressive. These tumors may harbor distinct molecular characteristics compared with cutaneous and mucosal melanoma of other sites. We analyzed the patterns of molecular, genomic, and protein changes in vulvar/vaginal melanoma (VM), and compared these changes with those of a large cohort of melanoma of nongynecologic origin. Methods: A total of 2,304 cases of melanoma submitted for molecular profiling from 2009 to 2015, including 51 VM cases, were reviewed. All tumors were analyzed using Illumina TruSeq Amplicon Cancer panel to search for sequence variants in genes commonly implicated in carcinogenesis. In situ hybridization and immunohistochemistry were also used to assess copy number and protein expression, respectively, of selected genes. Results: Of 51 cases of malignant VM, 14 originated from the vagina, 37 from the vulva. Fig. 1 summarizes the frequency of biomarkers of interest in VM, and NGM, which are further classified into cutaneous, acral, and mucosal based on site of origin. BRAF is most frequently mutated in VM (26%), compared with 36.6% in cutaneous melanoma and 8.3% (P = .008) in mucosal melanoma. However, BRAF mutations in VM are significantly less likely to include known responders to BRAF inhibitors than those from NGM tumors (P = .011). The c-KIT mutation rate in VM (22%) is significantly higher than cutaneous (3%, P b .001) and mucosal (8.8%, P = .05) melanoma. The majority (60%) of c-KIT mutations in VM are also known to be sensitive to inhibitors of tyrosine kinase receptor. NRAS mutations are rare in VM (4%) compared with cutaneous (25.9%, P = .009) and acral (40.6%, P = .002) melanoma. VMs express biomarkers of cytotoxic sensitivity more commonly than NGM, including increased TOP2A and RRM1, markers of anthracycline and gemcitabine resistance, respectively (P = .0001, 0.006). PDL1 is expressed frequently in both VM and NGM (56%, 63.5%), PI3KCAmutations, and ER/PR receptor expression are rare. Conclusions: Our findings suggest VM may represent a unique subclass of melanoma. VMs are unlikely to harbor mutations sensitive to existing BRAF inhibitors. Tyrosine kinase inhibitors or MEK inhibitors targeting c-KIT and NRAS may be of therapeutic benefit. PDL1 inhibitors warrant further exploration in patients with vulvovaginal melanoma.