The morphologic distinction of epithelioid mesothelioma from a reactive mesothelial proliferation can be difficult. Recent studies have demonstrated that serum osteopontin levels are increased in patients with mesotheliomas. We sought to determine if osteopontin expression is diagnostically helpful in distinguishing epithelioid mesothelioma from reactive mesothelial proliferations. We studied 7 cases of epithelioid mesothelioma and 20 cases of reactive mesothelial proliferations by immunohistochemical analysis using standard technique. All 7 mesotheliomas and 19 of 20 reactive mesothelial proliferations showed osteopontin expression. Osteopontin expression is not restricted to malignant mesothelial proliferations, and immunohistochemical analysis for osteopontin is not helpful in determining reactive vs malignant mesothelial proliferations. The reported usefulness of osteopontin as a serum tumor marker for mesothelioma may be due to differences in the amount or character of secreted protein in malignant mesothelioma compared with reactive mesothelial proliferations.