The distinction between reactive mesothelium and mesothelioma in pleural biopsy specimens is notoriously difficult, and conventional immunohistochemical markers have provided no relief. The object of this study was to examine the frequency of immunohistochemically detectable p53 overexpression in routinely processed, paraffin-embedded tissue from pleural mesotheliomas and from pleura showing reactive mesothelial hyperplasia, using a polyclonal antibody to formalin-resistant p53 epitopes, and to consider the diagnostic utility of this antibody in the distinction between mesothelioma and reactive mesothelium in pleural biopsy specimens. Immunostaining was enhanced by pepsin predigestion prior to the application of the primary antibody. Positivity occurred in 10/16 epithelial mesotheliomas, 9/19 biphasic mesotheliomas, 2/12 sarcomatous mesotheliomas but in none of 20 reactive pleura. Immunostaining was particularly intense in some of the biopsy specimens, which may be due to the rapidity with which these small pieces of tissue were fixed. In conclusion, this study suggests that p53 immunostaining can help to distinguish epithelial or biphasic mesothelioma from reactive mesothelial hyperplasia in formalin-fixed, paraffin-embedded pleural biopsy specimens.