Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication in patients receiving antiresorptive therapies for bone neoplastic localizations and osteoporosis. The aim of this study was to evaluate the clinicopathological features of MRONJ in a cohort of patients treated by new antiresorptive drugs (denosumab) and the corresponding outcome after 13-year maximum follow-up. Overall, 244 patients affected by MRONJ were treated from 2003 to 2015. After clinical and radiological examinations, all lesions were staged according to a dimensional staging system and then surgically treated. All the denosumab-related lesions were classified as stage II or III, thus requiring a more or less invasive surgical approach, despite the results of many recent studies, which suggested a conservative medical approach with early resolution for MRONJ in patients on denosumab. In the current series, 86.9% of treated lesions showed complete clinical and radiological healing, while 13.1% recurred; all recurrences were detected in patients who could not interrupt chemotherapy, steroids, and/or antiresorptive drugs administration due to their general conditions. In conclusion, all oral specialists should be aware of the MRONJ risk among patients taking new antiresorptive drugs; moreover, our protocol based on surgical treatment guided by dimensional staging could be considered effective in view of the low recurrence rate.