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. 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 (alpha = .05). 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. 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 Ver menos