Summary Synovial sarcoma of the pleural cavity is exceptionally rare and may be confused, both clinically and histologically, with malignant mesothelioma, with subsequent inappropriate therapy. To address this dilemma, four biphasic synovial sarcomas (BSSs) and four biphasic malignant mesotheliomas (BMMs) were studied with a panel of mucin and immunohistochemical stains to determine if they would allow one to distinguish between the two. The BMMs were all pleural-based. The BSSs were extrapleural. The mucin and immunohistochemical stains were all performed on formalin-fixed, paraffin-embedded tissue using standard techniques, with appropriate positive and negative controls. Mucin present in BSS is, in general, mucicarmine-positive and resistant to both hyaluronidase and diastase. Of the immune markers evaluated, only calretinin, Ber-Ep4 and bcl-2 were of limited discriminatory value. Subsets of cytokeratins, CEA and CD 34 were not helpful. With the exception of bcl-2, the apoptotic markers p53, bax and cpp32 (caspase) also were not useful. However, when the apoptotic stains were viewed collectively, variations in expression between the two tumours raised the possibility that alterations in apoptotic activity might be responsible for their pathogenesis and behavior. The diagnosis of BSS or BMM of the pleural should be made only after total consideration of clinical, radiological, histochemical and immunohistochemical findings. Although mucin stains are useful in differential diagnosis, reliance solely on immunohistochemical markers, with the possible exception of calretinin, Ber-Ep4 and bcl-2, is not dependable. The role of apoptosis in the pathogenesis of these tumours needs to be explored with a much larger series.