Medication-related osteonecrosis of the jaw (MRONJ) in cancer patients presents a considerable challenge in management. Current management is primarily based on interventions in a limited number of cases assessing a single approach. Medical management typically is reported to include antimicrobial therapy with or without surgery. Advances in the understanding of pathogenesis have led to the investigation of additional medical interventions for early-stage necrosis. We present 3 patients with advanced-stage MRONJ of the maxilla using combined medical modalities including antimicrobial therapy, photobiomodulation therapy, pentoxifylline, vitamin E, and synthetic parathyroid hormone. All patients had a good outcome and avoided surgical intervention. We also report biological and functional imaging that may assist in more effective diagnosis and management of MRONJ. The 3 patients reported suggest that combined medical management should be considered in all cases of MRONJ (including stage III) prior to determining if surgical intervention is required. Functional imaging with a technetium bone scan or positron emission tomography scan correlated with diagnosis and confirmed resolution in patients. We present 3 challenging MRONJ patients that were effectively managed with a combined medical and nonsurgical therapy that demonstrated good clinical outcomes avoiding surgical interventions.