BackgroundNevi of special sites (NOSS) are benign melanocytic lesions that occur at particular sites. Although the histological features of NOSS have been described, their immunophenotypic features have not been fully characterized. AimsTo present the clinicopathological characteristics of a case series of NOSS and to characterize their immunohistochemical profile. Materials and methodsThirty-five NOSS were assessed using immunoperoxidase staining techniques for the melanocytic (S100, Melan-A, and HMB45) and proliferation (Ki-67) markers. ResultsAll of the cases of NOSS showed concerning architectural changes (prominent lentiginous melanocytic proliferation, irregularities, crowdedness, and dyhesiveness of the nests), and cytological atypia (large nevomelanocytes with vesicular nuclei, clear cytoplasm, and dusty melanin pigment) that can lead to a misdiagnosis of atypical nevi or even melanomas. All of the cases of NOSS showed diffuse expression of S100 and Melan-A proteins. Ki-67 labeling index of the nevomelanocytes was extremely low. HMB45 protein expression was limited to the junctional and superficial dermal nevomelanocytes. ConclusionsNOSS can show histological features that can easily mimic atypical nevi or melanomas and this diagnostic consideration should be kept in mind to avoid their misdiagnosis. The expression of HMB45 protein in NOSS indicates that their nevomelanocytic cells have an activated phenotype. The decreased HMB45 protein expression following a gradient from junctional to deeper dermal localization in NOSS is indicative of their immunohistochemical maturation.