INTRODUCTION: The management of malignant pleural mesothelioma represents one of the most challenging issues in oncology, as there is no proven long-term benefit from surgery, radiotherapy or chemotherapy alone or in combination. Locoregional progression remains the major cause of death, but radical surgical resection may produce major postoperative morbidity. While radical or postoperative radiotherapy using conventional techniques has resulted in severe toxicity with no impact on survival, recent advances in radiotherapy delivery may be more effective. METHODS: We treated patients with locally advanced mesothelioma whose tumours had been sub optimally resected with high-dose three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) to large volumes of one hemithorax, using CT and positron emission tomography (PET) scan-based treatment planning. Clinical outcomes were assessed by determining patterns of failure and metabolic changes in total glycolytic volume (TGV) between pre- and post-irradiation( 18) F-FDG PET/CT scans and by recording acute and late toxicity grades. RESULTS: Fourteen patients were analysed with 40 PET scans performed before and up to 4.5years after radiotherapy. Eleven patients had pleurectomy/decortications, one had an extrapleural pneumonectomy and two had no surgery. Four patients who received chemotherapy had all progressed prior to radiotherapy. After radiotherapy, the in-field local control rate was 71%. No progression occurred in two patients, one was salvaged with further radiotherapy to a new site, four recurred inside the irradiated volume all with concurrent distant metastases and the other seven had distant metastases only. The TGVs were reduced by an average of 67% (range 12-100%) after doses of 45 to 60Gy to part or all of one hemithorax. There were no serious treatment-related toxicities. Median survival was 25months from diagnosis and 17months after starting radiotherapy. CONCLUSIONS: We have established that mesothelioma can be locally controlled with high radiation doses using 3DCRT or IMRT, and that strict normal tissue dose constraints have limited radiation toxicities. Radiotherapy should be considered to prevent or delay the local manifestations of progressive disease in suitable patients after surgery including extrapleural pneumonectomy and pleurectomy/decortication. Higher radiation doses may allow more effective palliation.