Medication-related osteonecrosis of the jaw (MRONJ) is an adverse side effect of drugs used to treat bone diseases. As the population continues to age with the aid of medications, MRONJ has been increasing in the case number and becomes an issue in dentistry. Until now, the pathophysiology of MRONJ is still unclear. A histological investigation of MRONJ specimens is a powerful tool to offer a broad view and basic knowledge of the disease. The knowledge gained from histological analysis might suggest meaningful directions for further research. In this study, 57 subjects, including patients with MRONJ, osteoradionecrosis of the jaw (ORN), osteomyelitis of the jaw (OM), and normal jaw bone, were studied. Hematoxylin and eosin-stained slides of these diagnosed cases were reviewed to confirm the diagnoses and to investigate the histologic features. Pearson’s chi-square test and Fishers’ exact test were performed to compare the histological features of 4 groups in pair. Logistic regression was fitted with multiple covariates to analyze the correlation. The results showed that MRONJ, ORN, and OM shared the characteristic feature of necrotic bone. The significant difference found between MRONJ and ORN was the presence of fibrous tissue (p<0.05), and between MRONJ and OM was the status of bacterial colonies (p<0.05). Although there was no significant difference in the presence of osteoclasts among groups, osteoclasts in MRONJ showed giant cells containing abnormal shaped and multi nuclei comparing with others. These findings suggest that there are differences in the histopathology of MRONJ and other necrotic diseases and these might be evidence to suggest the pathogenesis of MRONJ.