Deciduoid mesothelioma is a rare variant of epithelioid mesothelioma that was initially considered to occur exclusively in the peritoneum of young women who had no history of asbestos exposure and to be characterized by an aggressive clinical course, but it was later demonstrated that this tumor could also occur in the pleura of older men and women who had been exposed to asbestos. Some subsequent studies have also indicated that the clinical course is no different from that of conventional epithelioid mesothelioma. Herein are reported 21 cases of deciduoid mesothelioma that were investigated using a large panel of immunohistochemical markers, 9 of which were also studied by electron microscopy. Fifteen of the patients were male and 6 were female (mean age, 60 years). Seventeen of the cases originated in the pleura and four in the peritoneum. Histologically, all of the cases were composed of large, polygonal or ovoid cells with well-defined cell borders, dense eosinophilic cytoplasm, and single or multiple nuclei. In some cases, the cells exhibited a wide variation in their size and shape, frequent loss of cell cohesion, marked nuclear atypia, and high mitotic activity (>5 per 10 HPF); whereas, in others, the cells were more cohesive, less pleomorphic, and the mitotic activity low. As the survival of patients in the first group of cases was shorter (mean, 7 months), when compared with that of the latter (mean, 23 months), it is concluded that the differences in prognosis reported in deciduoid mesothelioma are due to the existence of a high-grade subgroup that presents highly aggressive clinical behavior. Therefore, when a high-grade deciduoid mesothelioma is present, it should be reported as it can significantly affect prognosis and treatment. The use of immunohistochemistry and electron microscopy in assisting in the differential diagnosis of deciduoid mesothelioma is also discussed.