Treatment of severe radiation burns remains a difficult challenge. Conventional surgical treatment (excision, skin grafting, skin or muscle flaps) often fails to prevent unpredictable and uncontrolled extension of the necrotic process. We report two clinical cases in which surgery was combined with mesenchymal stem cell (MSC) therapy. Clinical outcome was good and there was no recurrence of radiation inflammatory waves observed in the first patient after one year. This novel multi-disciplinary therapeutic approach, combining physical techniques, modern plastic surgery and cell therapy should improve the medical management of severe localized radiation burns.