The purpose of this randomized prospective study was to assess the efficacy of local radiotherapy in preventing malignant seeding along invasive diagnostic procedures (cytology, needle biopsy, thoracoscopy, or chest tube placement) in patients with malignant pleural mesothelioma. Forty consecutive patients with histologically proven malignant mesothelioma were enrolled. Twenty patients received three daily sessions of radiotherapy at a dosage of 7 Gy 10 to 15 days after thoracoscopy. The other 20 patients did not receive radiotherapy. None of the 20 patients treated developed entry tract metastasis. In contrast, 8 of the 20 (40%) patients who were not treated developed metastases. These findings confirm the efficacy and safety of early local radiotherapy in preventing malignant seeding after invasive diagnostic procedures in patients with malignant pleural mesothelioma.