Differentiation of sarcomatoid mesothelioma from other sarcomatoid tumors involving the pleura and other structures by light microscopy remains an important diagnostic challenge for surgical pathologists. The purpose of the present study was to investigate the utility of diagnostic immunohistochemistry for differentiating sarcomatoid mesothelioma from its histological mimics: true sarcoma and pulmonary sarcomatoid carcinoma. A total of 39 specimens of mesotheliomas with sarcomatoid components, 43 specimens of true sarcomas, and nine specimens of pulmonary sarcomatoid carcinomas were obtained from Japanese patients and examined using a 10-antibody panel (calretinin, WT1, AE1/AE3, CAM5.2, epithelial membrane antigen, desmin, alpha-smooth muscle actin, S-100 protein, CD34, and CD68). CAM5.2 had the highest sensitivity and specificity for differentiating sarcomatoid mesothelioma from true sarcoma. The combination of CAM5.2, WT1, and AE1/AE3 is recommended for routine pathological diagnosis. Accurate clinical information is necessary for differentiating sarcomatoid mesothelioma from sarcomatoid carcinoma.