Background Oral melanocytic neoplasms pose a diagnostic challenge to pathologists owing to their rarity relative to those in the skin. The utility of PRAME in distinguishing nevi from melanomas has been established in the skin, but limited information exists regarding its usefulness in the oral cavity. Methods Thirty‐five previously diagnosed pigmented oral lesions were retrospectively evaluated with PRAME. The lesions consisted of 16 oral nevi, 10 melanomas, and 10 melanotic macules. Results Strong and diffuse nuclear PRAME staining was observed in all but one of the oral melanomas, which showed no staining. No nuclear PRAME staining was observed in any of the oral nevi or melanotic macules. Conclusions PRAME is a useful tool in the evaluation of oral melanocytic neoplasms. Our data indicate that PRAME is a highly specific but incompletely sensitive marker of oral melanoma. Larger studies could further illuminate the diagnostic value of PRAME in oral lesions.