A case of mesothelioma with a small cell component in a 53-year-old, non-smoker woman. The patient had a history of asbestos exposure, and presented with thoracic pain. A total body computed tomogram showed a left pleural effusion and a 7.5-cm pleural mass. Thoracoscopy revealed a diffuse nodular thickening of the left parietal pleura, and a biopsy was performed. The patient died of the disease 4 months after diagnosis. Microscopically, the pleural neoplasm was composed of three different components: 40% of the tumor showed the classic histology of a malignant epithelial mesothelioma, 40% was composed of small- to medium-sized cells with open nuclear chromatin, evident nucleoli and high mitotic activity, and 20% of the neoplasm was indistinguishable from a small cell carcinoma. Immunohistochemically, the first component was diffusely and strongly positive for cytokeratin AE1/AE3, cytokeratin CAM 5.2 and EMA, focally positive for BER-EP4, and negative for CD15, B 72.3, CEA, LCA, chromogranin, synaptophysin, TTF-1 and CD99. The cells of the second component were positive only for cytokeratin AE1/AE3 and cytokeratin CAM 5.2, and the elements of the third component were negative for all the antibodies tested. Pleural mesothelioma with a small cell component is rare. The most useful parameters to distinguish it from other small cell malignancies that may involve the pleura, particularly small cell carcinoma of pulmonary origin, are discussed.