The role of immunohistochemical markers in distinguishing peritoneal mesothelioma from primary or metastatic serous papillary carcinoma of the peritoneum was evaluated. We immunostained 20 peritoneal mesotheliomas (from 14 men and 6 women), 14 primary peritoneal carcinomas, and 14 metastatic serous ovarian carcinomas with a panel of 16 antibodies. Positive staining for calretinin was identified in 17 (85%) of 20 mesotheliomas, but all carcinomas were negative. Positive staining for Ber-EP4 was identified in 27 (96%) of 28 carcinomas and in 2 (10%) of 20 mesotheliomas. Estrogen receptors were positive in 26 (93%) of 28 carcinomas, and progesterone receptors were positive in 8 (29%) of 28 carcinomas. All mesotheliomas were negative for estrogen and progesterone receptors. The other antibodies evaluated were insufficiently sensitive and/or specific to be diagnostically useful. In conjunction with calretinin and Ber-EP4, estrogen and progesterone receptors are useful discriminatory markers for distinguishing peritoneal mesothelioma from primary or metastatic serous carcinoma.