Purpose. Using the example of a clinical case, show the difficulties of differential diagnosis in atypical course of pleural tuberculous empyema, when X-ray examination data is more characteristic of pleural mesothelioma. Materials and methods. The clinical observation is given. A retrospective analysis of the data of laboratory and instrumental studies, as well as carrying out the necessary set of additional diagnostic procedures in St. Petersburg Scientific Research Institute оf Phthisiopulmonology allowed to properly put the final diagnosis and choose the optimal treatment to the patient. Results. The present clinical observation has demonstrated the difficulty of differential diagnosis of tuberculous empyema and pleural mesothelioma, as well as the need for additional diagnostic procedures in order to reliably exclude the presence of cancer process in a given clinical case. Conclusion. Conducting a comprehensive examination of the patient in combination with the methods of morphological verification and comprehensive microbiological examination allows you to verify the correct diagnosis and prescribe adequate therapy.