Introduction: Malignant pleural mesothelioma is a malignant tumor of mesothelial origin, the diagnosis and treatment of which still represent a challenge. OCT4, NANOG and SOX2 are pluripotency factors whose activity is crucial for the processes of cell division and maturation during embryonic development, and which are being investigated for their role during oncogenesis. The PI3K/AKT/BCL2 signaling pathway is one of the better-studied intracellular signal transmission cascades, with the activity of which cancer cells avoid the processes of apoptosis and thus enable their survival. Materials and methods: The study used samples from patients with malignant pleural mesothelioma. Immunohistochemical and PCR analyzes were performed to detect proteins or genes of the pluripotency factors OCT4, NANOG and SOX2 and the PI3K/AKT/BCL2 pathway. Results: In this study, we demonstrated the activity of pluripotency factor proteins and genes in pleural mesothelioma and in healthy mesothelium. NANOG, SOX2 and OCT4 gene activity was higher in mesothelial cells, while protein expression was higher in mesothelioma cells. NANOG expression is associated with a less differentiated subtype of mesothelioma. In the research, we showed the expression of PI3K and AKT and BCL2 in mesothelioma and in the pleura, whereby gene activity was higher in pleural cells, and AKT and BCL2 proteins in mesothelioma cells. Patients with sarcomatoid and pleomorphic mesothelioma had the worst survival, while the influence of the expression of NANOG, OCT4 and SOX 2 and PI3K and AKT on survival was not proven. Conclusion: We conclude that the above signaling mechanisms are active in pleural mesothelioma, and additional research is needed to reveal precise predictive factors in this disease.