The histologic distinction between epithelial peritoneal mesothelioma and papillary serous carcinoma diffusely involving the peritoneum may be difficult. Although some investigators have indicated that immunohistochemistry can facilitate this differential diagnosis, only a few studies using a limited number of markers have been published. In this study, the immunoreactivity of keratin 5/6, vimentin, epithelial membrane antigen, thrombomodulin, calretinin, MOC-31, Ber-EP4, carcinoembryonic antigen, TAG-72 (B72.3), CD15 (Leu-M1), placental alkaline phosphatase, CA19-9, CA-125, HBME-1, 44-3A6, and S-100 protein was investigated in 35 epithelial peritoneal mesotheliomas, and 45 papillary serous carcinomas [30 ovarian (10 primary and 20 metastatic to the peritoneum) and 15 papillary serous carcinomas of the peritoneum]. After analyzing the results, it is concluded that calretinin, thrombomodulin, and keratin 5/6 are the best positive markers for differentiating epithelial malignant mesotheliomas from papillary serous carcinomas diffusely involving the peritoneum. The best diagnostic discriminators among the antibodies considered to be negative markers for mesothelioma are MOC-31, B72.3, Ber-EP4, CA19-9, and Leu-M1. Immunostaining for carcinoembryonic antigen, placental alkaline phosphatase, epithelial membrane antigen, vimentin, HBME-1, 44-3A6, CA-125, or S-100 have little or no diagnostic utility in establishing the differential diagnosis between these conditions. The results of this study also confirm previous observations indicating that both papillary serous carcinomas of the peritoneum and serous carcinomas of the ovary have a similar phenotype and, therefore, immunohistochemical studies are not useful in separating these entities.