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Aim: Unlike most other malignancies, malignant pleural mesothelioma (MPM) has a tendency to recur along tracks of chest wall instrumentation. We investigated the efficiency of hypofractionated radiotherapy for prevention of malignant seeding. Methods: Twenty-one (six female, 15 male) patients diagnosed with pleural mesothelioma who had chest wall instrumentation and were treated with prophylactic radiotherapy were investigated retrospectively. All patients underwent surgery or thoracoscopy and/or talc pleurodesis, for diagnosis, staging procedures or as a treatment. All were treated with electron (12 MeV) external beam radiation therapy (21 Gy in three fractions over 3 days), directed to the instrumentation pathway after the invasive procedure. After completion of radiotherapy, four of 21 patients had also undergone chemotherapy. Results: Nineteen of 21 patients were followed-up for a median period of 13 months (1–24 months) and two patients were lost just after the first month of the follow-up period. None of the followed patients had tumor progression in the treated area. Radiotherapy was well tolerated. The most common side-effect was grade 1 erythema (Radiation Therapy Oncology Group [RTOG] scale), noted in 13 treated patients. Conclusion: Our experience showed that prophylactic radiotherapy to prevent malignant seeding in malignant mesothelioma at invasive procedure sites was effective and well tolerated in preventing malignant seeding, painful metastases after surgery or instrumentation in patients with pleural mesothelioma. Larger multicenter prospective trials are still needed to validate this treatment approach utility for it to be recommended routinely.