Abstract The purpose of this study was to compare medication-related osteonecrosis of the jaw (MRONJ) with osteoradionecrosis (ORN). Group 1 comprised 74 MRONJ patients (93 lesions) and group 2 comprised 59 ORN patients (69 lesions). Patient characteristics, clinical presentation of the lesions, the presence of complications, and the relationship with previous dental extractions were analyzed for both groups. Significant differences were found between the groups with regard to the characteristics of the patient populations, extraction as the precipitating event, the type of initial complaint, the prevalence of pain, and the location of the lesions. In the ORN group, significantly more patients complained of pain ( P = 0.0108) compared with the MRONJ group. Furthermore, significantly more pathological fractures ( P < 0.0001) and skin fistulae ( P < 0.0001) occurred in the ORN group. The treatment was more often conservative in the MRONJ group than in the ORN group (61.3% vs. 36.2%). Despite similarities in terms of imaging, risk factors, prevention, and treatment, MRONJ and ORN are two distinct pathological entities, as highlighted by the differences in patient characteristics, the initial clinical presentation, course of the disease, and outcome.