BACKGROUND: Melanoma is a malignant neoplasm that arises from melanocytes, which are melanin-producing cells primarily found in the skin. Although rare, melanoma is highly aggressive. In 2023, 13,270 cases of skin melanoma were identified in Russia. The primary risk factor is excessive exposure to ultraviolet radiation. Immunohistochemical studies using markers such as HMB-45 (Human Melanoma Black-45), Melan-A/MART-1 (Melanoma Antigen Recognized by T Cells 1), and S100 are crucial for diagnosing skin melanoma, improving the accuracy of tumor detection, and optimizing treatment. AIM: This study aimed to assess the prognostic significance of melanocytic markers HMB-45, Melan-A/MART-1, and S100 in skin melanoma, taking into account tumor histological subtypes and stages according to the pTNM classification. METHODS: Skin melanoma samples from patients (n = 117) were assessed using immunohistochemistry with antibodies to HMB-45, Melan-A/MART-1, and S100. The results were interpreted based on the histological subtype of the tumor and the Breslow thickness, which was used to determine the disease stage. RESULTS: The count of atypical melanoma cells, considering the histological subtype of the tumor, showed that the S100 marker had the highest sensitivity (91.2%) compared to Melan-A/MART-1 and HMB-45, especially in desmoplastic melanoma. Moreover, S100 and Melan-A/MART-1 demonstrated stable staining regardless of the degree of invasion, whereas the number of HMB-45-positive atypical melanocytes increased as the tumor progressed according to the pTNM classification. CONCLUSION: Immunohistochemical analysis of various histological subtypes of skin melanoma revealed stable expression of S100, Melan-A/MART-1, and HMB-45 proteins in superficial spreading and nodular tumors. In desmoplastic melanoma, the expression of Melan-A/MART-1 and HMB-45 was absent, whereas S100 expression remained. The proportion of S100- and Melan-A/MART-1-positive atypical cells was independent of the degree of tumor invasion (according to pTNM stages). The percentage of HMB-45-positive atypical melanocytes increased proportionally with the thickness of invasion, supporting its prognostic significance.