Malignant pleural mesothelioma (MPM) is a generally fatal disease with no standard treatment. There are encouraging reports using intraperitoneal chemotherapy to treat peritoneal mesotheliomas and intrapleural chemotherapy (IPC) to treat malignant pleural effusions. Our objective was to evaluate the efficacy of IPC after subtotal pleurectomy. Between 1988 and 1992, 20 consecutive patients with diffuse MPM limited to one hemithorax underwent subtotal pleurectomy. Thirteen patients with biopsy-proven MPM known prior to thoracotomy were enrolled in a phase II combined modality protocol consisting of perioperative intrapleural cisplatin (100 mg/m2) and ara-C (1,200 mg) after subtotal pleurectomy, followed by systemic cisplatin (50 mg/m2/week x 8) and mitomycin-C (8 mg/m2, days 1 and 36). Seven patients with MPM could not be enrolled because their diagnosis was made post-thoracotomy. These patients underwent subtotal pleurectomy with (n = 4) or without (n = 3) adjuvant radiation (4,500-5,000 cGy in 3 patients, 2,100 cGy in 1 patient). One of three patients who developed chemotherapy-related nephrotoxicity died, the only treatment-related mortality. All 3 patients requiring postoperative readmission received IPC. Significant morbidity did not occur in patients not receiving chemotherapy. Median survival and time to progression were significantly longer in patients not receiving IPC (21 vs. 9 months, P = 0.04; 12 vs. 6 months, P = 0.01). In conclusion, intrapleural and postoperative systemic chemotherapy resulted in significant toxicity and did not improve survival in our patients who underwent subtotal pleurectomy for MPM.