To assess the diagnostic accuracy of combinations of antibodies in the differential diagnosis of metastatic carcinomas and mesotheliomas in pleural lesions. The specificity and sensitivity of the commercially available antibodies Ber-EP4, MOC-31, CEA, B72.3, CD15, E-cadherin and calretinin were evaluated using an indirect immunoperoxidase staining technique. This technique was applied to formalin-fixed, paraffin-embedded tissue blocks of pleural lesions. Twenty-one patients with metastatic carcinoma (MC) and 20 patients with malignant mesothelioma (MM) were included. The combination E-cadherin/calretinin had the highest specificity (MC 100% and MM 91%) and sensitivity (MM 100% and MC 91%) considering both categories of tumours. The combination of E-cadherin/calretinin appears to be a suitable panel for distinguishing metastatic carcinomas and mesotheliomas in pleural lesions. The additional value of other markers is limited.