Epidermal growth factor receptor (EGFR) is overexpressed in a variety of epithelial malignancies. In lung cancer cases, EGFR gene mutation at the kinase domain and EGFR gene amplification are reported to be predictors of the response to EGFR tyrosine kinase inhibitors. In malignant pleural mesothelioma (MPM), the role of EGFR is less clear. We studied EGFR gene mutation, amplification and protein expression in 25 Japanese patients with MPM. None had previously reported EGFR mutations detected by the TaqMan PCR assay. Using immunohistochemistry, 8/25 (32%) cases were positive for the EGFR protein. The cases of sarcomatous type and desmoplastic type were all negative. Fluorescence in situ hybridization analysis revealed three low polysomy cases and one high polysomy case. The low polysomy cases included one biphasic type and two epithelial types, and the high polysomy case was epithelial type. These four cases expressed EGFR protein. In MPM, EGFR seems to play a role in a limited subset of patients. To identify possible candidates for EGFR tyrosine kinase in inhibitor therapy, the information on the EGFR gene status may be valuable.