Differential diagnosis between mesothelioma and angiosarcoma remains challenging because of their overlapping morphological and immunohistochemical phenotypes. Angiosarcoma may show both epithelioid and sarcomatoid morphology and is occasionally a cytokeratin-expressing tumor as with mesothelioma. Generally, endothelial markers are always expressed by angiosarcoma but not by mesothelioma; however, a subset of mesothelioma expresses endothelial markers, making the usefulness of these markers limited. Currently, little information is available about the immunoreactivity of mesothelioma to endothelial markers. Therefore, we investigated immunoreactivities of mesothelioma and angiosarcoma to endothelial markers and sought to identify a useful marker in their differential diagnosis. We enrolled 147 cases of pleural mesothelioma, comprising 93 epithelioid, 25 biphasic, and 29 sarcomatoid subtypes. For comparison, we used 41 cases of angiosarcoma occurring in various organs. Using a tissue block showing the representative morphology, the expressions of endothelial (CD31, CD34, factor-VIII, ERG, and claudin-5) and of mesothelial markers (calretinin, WT-1, CK5/6, and EMA) were evaluated by immunohistochemistry. Calretinin and WT1 were expressed in 82.2% (120/146) and 82.9% (116/140) cases of mesothelioma, respectively. Among the three subtypes of mesothelioma, the immunoreactivity of sarcomatoid mesothelioma to calretinin was relatively low with the positivity of 48.3% (14/29). Calretinin was expressed in none of the angiosarcoma cases (0/41), whereas WT-1 was expressed in 4.9% (2/41) cases of angiosarcoma. Conventional endothelial marker (CD31, CD34, factor VIII, and ERG) were expressed in 10.3% (15/146), 3.5% (5/142), 3.4% (5/146), and 29.1% (39/134) cases of mesothelioma, respectively. The immunoreactivities of sarcomatoid mesothelioma to conventional endothelial markers were relatively high with the positivity of 31.0% (9/29) for CD31, 7.1% (2/28) for CD34, 10.7% (3/28) for factor VIII, and 56.0% (14/25) for ERG. Claudin-5 expression was observed in all the angiosarcoma cases (36/36), but in none of the mesothelioma cases (0/138). We showed overlapping immunophenotypes between mesothelioma and angiosarcoma. Endothelial markers, except for claudin-5, were more frequently expressed than expected by mesothelioma, especially by sarcomatoid mesothelioma. High sensitivity and specificity of claudin-5 in the distinguishment of angiosarcoma from mesothelioma suggest the usefulness of this marker, indicating that claudin-5 should be included in a panel of immunohistochemical markers in the differential diagnosis between mesothelioma and angiosarcoma.