Objective: The purpose of this manuscript is to present a clinicopathologic review of the literature concerning all the detailed cases of primary oral melanoma (OM) that were confirmed by immunohistochemistry. In addition, a pertinent case presentation is addressed. Data Sources: An extensive electronic search of the literature was performed using PubMed/Medline from 1953 to 2017. Relevant articles were selected based on specific inclusion criteria. Statistical analyses were conducted by the Shapiro-Wilk, Fisher's exact, chi-square, and Z tests (α = .05). Results: Forty-nine cases of primary OM reported in the literature plus the current case were analyzed; patient ages ranged from 17 to 89 years with a mean of 60.8 years; male to female ratio was 1.5:1; Caucasian patients were the most affected and the most frequent locations were maxillary alveolar mucosa and palate; the majority of the lesions were pigmented (62%); differences among the proportions of positivity to S-100, HMB-45, Melan-A, NKFC3, vimentin, tyrosinase, CK, microphthalmia transcription factor (MITF), and Ki-67 were found (P .0001), especially when comparing with vimentin (P .05) and CK (P .01); recurrence was reported in 11.6% and mortality in 54.8%. The case presented is of a 71-year-old mixed-race woman who presented multiple pigmented lesions over the maxillary alveolar mucosa and palate. Positivity for S-100, HMB-45, Melan-A, and Ki-67 confirmed the diagnosis of primary OM. Conclusion: Primary OM is rare and very aggressive, with only 49 detailed cases confirmed by immunohistochemistry existing within the English literature, in addition to the present case. S-100 and HMB-45 are excellent markers to confirm the diagnosis of primary OM, although the use of adjuvant specific markers such as Melan-A, tyrosinase, and MITF should be also encouraged. Keywords: immunohistochemistry, melanocyte, melanoma, oral cancer