Distinguishing malignant mesotheliomas from benign mesothelial proliferations on hematoxylin and eosin-stained sections can be extremely challenging. Various immunohistochemical stains have been suggested to help in making this distinction, but all are controversial. Recently, IMP3 (insulin-like growth factor II mRNA binding protein 3) and GLUT-1 (glucose transporter protein 1) have been proposed as immunohistochemical markers that are positive in mesotheliomas but not in benign proliferations. We evaluated the performance of these markers on a tissue microarray containing 30 malignant mesotheliomas and 48 benign thoracic or abdominal mesothelial proliferations. IMP3 was positive in 53% of malignant and 27% of benign cases (P=0.03), whereas GLUT-1 was positive in 60% of malignant and 13% of benign cases (P=0.0003). Forty-three percent of malignant cases, but only 4% of benign cases, were positive for both IMP3 and GLUT-1 (P=0.00003). We conclude that, statistically, both IMP3 and GLUT-1 are more frequently positive in malignant compared with benign mesothelial processes; however, the frequency of positive staining in benign cases is too high to allow their diagnostic use as single stains. The combination of both markers may be of greater diagnostic value, but this hypothesis should be confirmed in further studies.