Malignant mesotheliomas of the testis arise from the tunica vaginalis, formed from the evagination of the abdominal peritoneum into the scrotum. The immunohistochemical profile of the tunica vaginalis and associated neoplasms is often extrapolated from thoracic studies. Testicular series are uncommon, usually derived from previous case studies and literature reviews. The immunohistochemical findings in 20 cases originally diagnosed as malignant mesotheliomas are presented. Archival testicular malignant mesothelioma specimens from 1959 to 2004 were collected from hospitals throughout the United Kingdom and from the authors' own archives. Hematoxylin and eosin-stained sections were reviewed, and selected sections from each case were then examined using an immunohistochemical panel of eight antibodies: calretinin (Zymed, 1:200), epithelial membrane antigen (EMA) (DAKO, 1:50), thrombomodulin (DAKO 1:5), CK7 (DAKO, 1:100), CK5-CK6 (DAKO, 1:10), BerEp4 (DAKO, 1:25), carcinoembryonic antigen (CEA) (DAKO, 1:10), and CK20 (DAKO, 1:100). The EnVision technique was used for all antibodies. Sections were reviewed independently by three pathologists. Electron microscopy was performed on selected cases. In all cases, the morphologic light microscopy criteria for a diagnosis of malignant mesothelioma were present. However, two tumors were later excluded from the study because of diffuse strong positive immunostaining with CK20 and BerEp4 and an ultrastructural appearance of adenocarcinoma. Of the remaining cases, 15 of 18 (83%) were purely epithelioid in type, showing a mixture of papillary, tubular, and solid patterns, and 3 of 18 (17%) showed a mixed sarcomatoid/epithelioid pattern. All cases were positive for calretinin and EMA (100%), 16 of 18 (89%) were positive for thrombomodulin, and 15 of 18 (83%) were positive for CK7. CK5-CK6 positivity was present in 13 of 18 (72%) but varied in strength and distribution; 2 of 18 (11%) were positive for BerEp4. All the cases were negative for CK20 and CEA. Four of the 18 cases were examined by electron microscopy, which revealed long thin microvilli supporting a diagnosis of malignant mesothelioma. This study has shown that the immunocytochemical profile of testicular malignant mesotheliomas is similar to those arising in the pleura, with diffuse positivity for calretinin, EMA, thrombomodulin, and CK7, and negative for CK20 and CEA. Focal weak positivity may be encountered with BerEp4. However, histopathologists should be aware of the variability in CK5-6 staining in testicular specimens when compared with pleural mesotheliomas.