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Malignant mesothelioma (MM) is a rare tumor of mesothelial cells, with an increasing incidence both in developed and developing countries. MM has three major histological subtypes, in order of frequency, according to the World Health Organization (WHO) Classification of 2021: epithelioid, biphasic, and sarcomatoid MM. Distinction may be a challenging task for the pathologist, due to the unspecific morphology. Here, we present two cases of diffuse MM subtypes to emphasize the immunohistochemical (IHC) differences, and to facilitate diagnostic difficulties. In our first case of epithelioid mesothelioma, the neoplastic cells showed cytokeratin 5/6 (CK5/6), calretinin, and Wilms‐tumor‐1 (WT1) expression, while remaining negative with thyroid transcription factor‐1 (TTF‐1). BRCA1 associated protein‐1 (BAP1) negativity was seen in the neoplastic cells' nucleus, reflecting loss of the tumor suppressor gene. In the second case of biphasic mesothelioma, expression of epithelial membrane antigen (EMA), CKAE1/AE3, and mesothelin was observed, while WT1, BerEP4, CD141, TTF1, p63, CD31, calretinin, and BAP1 expressions were not detected. Due to the absence of specific histological features, the differentiation between MM subtypes could be a challenging task. In routine diagnostic work, IHC may be the proper method in distinction. According to our results and literature data, CK5/6, mesothelin, calretinin, and Ki‐67 should be applied in subclassification. [ABSTRACT FROM AUTHOR]