To evaluate the expression of the intermediate filament desmin in reactive mesothelium and malignant mesothelioma and to compare its utility with five other previously reported immunomarkers claimed to be of use in distinguishing reactive from neoplastic mesothelium. Sixty cases of malignant pleural mesothelioma and 40 cases of reactive mesothelial hyperplasia formed the study group. Cases were immunohistochemically stained with desmin, epithelial membrane antigen (EMA), p53, Bcl-2, P-glycoprotein and platelet-derived growth factor receptor (PDGF-R) beta-chain by the avidin-biotin complex method. The cohort of malignant pleural mesotheliomas were immunoreactive to desmin, EMA and p53 in 6/60 (10%), 48/60 (80%) and 27/60 (45%), respectively. In comparison, the cohort of reactive mesothelial hyperplasias were immunoreactive to desmin, EMA and p53 in 34/40 (85%), 8/40 (20%) and 0/40 (0%), respectively. In a smaller cohort (n = 15) of malignant pleural mesotheliomas, Bcl-2, P-glycoprotein and PDGF-R beta-chain were expressed in 0/15 (0%), 2/15 (13%) and 15/15 (100%), respectively. In a small cohort (n = 15) of reactive mesothelial hyperplasias, Bcl-2, P-glycoprotein and PDGF-R beta-chain were immunoreactive in 0/15 (0%), 0/15 (0%) and 6/15 (40%), respectively. Desmin and EMA appear to be the most useful markers in distinguishing benign from malignant mesothelial proliferations. Desmin appears to be preferentially expressed in reactive mesothelium and EMA appears to be preferentially expressed in neoplastic mesothelium. The complementary use of both markers is advocated in ascertaining the nature of mesothelial proliferations. Immunohistochemical detection of mutated p53 oncoprotein appeared to be of less utility in this study on account of the low marker sensitivity for malignant mesothelioma. However, p53 antibody may be of use as a second-line marker of neoplastic mesothelium within a standard immunohistochemical panel of antibodies. In this study, Bcl-2, P-glycoprotein and PDGF-R beta-chain appear to be of no use in distinguishing reactive from neoplastic mesothelium, although more formal evaluation of these markers is required.