The purpose of this investigation was to analyze the volume of medication-related osteonecrosis of the jaw (MRONJ) lesions by semi-automatic segmentation of cone-beam computed tomography images, and correlate the results with the underlying diseases and applied medication. MRONJ lesions detected in cone-beam computed tomography images were assessed. The open-source software ITK-Snap enabled volumetric measurements of MRONJ lesions based on semi-automatic segmentation. Results were analyzed according to necrosis volume, localization, and gender. In addition, the underlying disease and the type of application of antiresorptive medication were investigated. Cone-beam computed tomography images of 66 patients were studied. 34 male and 32 female patients were included, with ages ranging from 50 to 93 years at the time of diagnosis. The mean volume was 993.24 ± 620.94 mm3: 484.73 ± 230.97 mm3 for the upper jaw and 1084.04 ± 625.74 mm3 for the lower jaw. The results indicated statistically significant differences between lesions of the upper and lower jaw, regardless of gender (p = 0.003). The analysis of differences between males and females did not show any significant results (p = 0.464), although males presented slightly larger lesions than females. With regard to the underlying disease, patients with osteoporosis presented larger volumes, whereas patients with malignant tumors presented smaller volumes. Nevertheless, no statistically significant differences according to the underlying disease (p = 0.313) were detected. However, patients with intravenous (iv) application showed statistically significantly larger lesions than patients who underwent oral or subcutaneous (s.c.) applications (p = 0.004). It seems that the osteonecrosis volume correlates with the applied antiresorptive agents. Larger MRONJ lesions should be expected in patients who receive intravenous antiresorptive therapy.