Objectives/Hypothesis PENTOCLO treatment, associating pentoxifylline, tocopherol, and clodronate, resolves radiation‐induced fibrosis. The main aim of the present study was to prospectively assess efficacy in mandibular osteoradionecrosis (ORN). Study Design Prospective cohort study. Methods Twenty‐seven patients with mandibular ORN were included in the Pentoclauvergne Study between January 2014 and February 2016. After an initial 28‐day phase of antibiotic, antifungal, and corticosteroid therapy, they received the PENTOCLO association daily until cure or a maximum of 24 months. The main assessment criterion was exposed bone area (EBA); secondary criteria comprised the Subjective, objective, management, and analytic (SOMA) score. Results Under PENTOCLO, EBA decreased by 28% at 2 months, 55% at 6 months, and 92% at 24 months; the SOMA score decreased by 23%, 38%, and 50%, respectively. A complete treatment course cured 76.5% of patients at a mean 9.6 months. Conclusions PENTOCLO is a simple, well‐tolerated, and effective treatment for mandibular ORN. Level of Evidence 4 Laryngoscope, 130:E559–E566, 2020