Background and objective This retrospective study was designed to evaluate the response and survival of malignant pleural mesothelioma to radiotherapy when delivered with surgery and chemotherapy and when delivered alone or with chemotherapy. Methods A study for 110 patients with malignant pleural mesothelioma who presented to radiotherapy department, National Cancer Institute, Cairo and received radiation therapy in the period from January 1999 to July 2007. Results Forty-six patients (41.8%) received trimodality therapy (surgery & adjuvant or neoadjuvant chemotherapy & adjuvant radiotherapy), while bimodality therapy (chemotherapy & radiotherapy) in 38 patients (34.5%), while 26 patients (23.6%) received single modality therapy (palliative radiotherapy), 22 patients (20%) developed local recurrence, 22 patients (20%) developed distant metastases months, 14 patients (12.7%) developed local disease progression, 25 patients (22.7%) are still alive and free of disease at time of reporting. The median survival for all patients was 16 months, while 12 and 18 months overall survival were 63.6% & 31.8% respectively while median survival for stage II, III, IV patients was 16.5, 12.5 and 8 months respectively. Conclusion Multimodality approach involving surgery, chemotherapy and radiotherapy have been evaluated and proved its superiority in improving survival, especially in stages II.