We examined benign and malignant mesothelial tissue samples for the presence of X-linked inhibitor of apoptosis protein (XIAP), a potent constituent of the inhibitor of apoptosis family of caspase inhibitors. We subjected 55 sections (31 malignant mesotheliomas, 2 well-differentiated peritoneal mesotheliomas, 13 pleural mesothelial hyperplasias, and 9 benign mesothelial tissues) from archival formalin-fixed, paraffin-embedded surgical tissue blocks to citrate-based antigen retrieval and then incubated them with monoclonal anti-XIAP (clone 48, dilution 1:250; BD Biosciences, San Jose, CA) at 4 degrees C for 72 hours and developed them using EnVision-Plus reagents (DAKO, Carpinteria, CA) and diaminobenzidine as the chromogen. Particulate or nonhomogeneous cytoplasmic staining was considered positive. All 9 normal mesothelial samples were negative for XIAP. Of 13 mesothelial hyperplasias, 1 (8%) was weakly positive in fewer than 10% of cells, as was 1 of 2 well-differentiated peritoneal mesotheliomas. Of 31 malignant mesotheliomas, 25 (81%) displayed XIAP positivity. XIAP immunostaining, when strong, allows for distinction of malignant from benign and hyperplastic mesothelial cell populations and is a potentially useful immunodiagnostic marker in small samples and morphologically controversial cases. Elevated expression of XIAP could contribute to tumorigenesis in mesothelioma.