Osteoradionecrosis (ORN) is one of the most severe complications after head and neck radiotherapy. Once established, ORN is difficult to manage and is traditionally considered to be irreversible. Since the recent understanding of the pathophysiology of ORN is based on the concept of radiation-induced fibrosis, a new therapeutic medical regimen has been proposed comprising the combination of pentoxifylline, tocopherol and clodronate (PENTOCLO). A 55-year-old woman presented with grade III ORN with large intraoral bone exposure, a fracture of the left posterior horizontal branch and an orocutaneous fistula. Because she refused surgery, medical treatment with PENTOCLO was proposed. After 55months of treatment, there was complete mucosal coverage and complete consolidation of the fracture site around the orocutaneous fistula. PENTOCLO treatment can help some patients with grade III disease, as in this case. Further prospective randomized controlled trials are needed to confirm this result.