This is the first case report where two patients were under uniform denosumab administration protocol in diffuse sclerosing osteomyelitis (DSO) treatment and were closely monitored for 18 months. Objectives: This study aimed to describe the beneficial effects of denosumab in DSO treatment as well as pain relief and the significant lack of long-term use due to poorer outcomes after repeated use. DSO of the jaw is a poorly understood rare chronic disease the treatment of which is still very challenging despite a rapid development of medicine. Different medical treatments have been proposed without any significant long-lasting success. Bisphosphonates have offered substantial clinical benefit in DSO therapy, but due to harmful pharmacodynamic properties, denosumab therapy has been used to replace bisphosphonate therapy. Patients had a reduction in pain intensity with each subsequent application of denosumab but with less success than the first administration of denosumab. This case report has shown that denosumab could be a promising conservative treatment option for pain treatment in patients suffering from DSO.