Objectives: To identify two novel three-dimensional (3D) cephalometric landmarks and create a novel three-dimensionally based anteroposterior skeletal measurement that can be compared with traditional two-dimensional (2D) cephalometric measurements in patients with Class I and Class II skeletal patterns. Materials and Methods: Full head cone-beam computed tomography (CBCT) scans of 100 patients with all first molars in occlusion were obtained from a private practice. InvivoDental 3D (version 5.1.6, Anatomage, San Jose, Calif) was used to analyze the CBCT scans in the sagittal and axial planes to create new landmarks and a linear 3D analysis (M measurement) based on maxillary and mandibular centroids. Independent samples t-test was used to compare the mean M measurement to traditional 2D cephalometric measurements, ANB and APDI. Interexaminer and intraexaminer reliability were evaluated using 2D and 3D scatterplots. Results: The M measurement, ANB, and APDI could statistically differentiate between patients with Class I and Class II skeletal patterns (P , .001). The M measurement exhibited a correlation coefficient (r) of 20.79 and 0.88 with APDI and ANB, respectively. Conclusions: The overall centroid landmarks and the M measurement combine 2D and 3D methods of imaging; the measurement itself can distinguish between patients with Class I and Class II skeletal patterns and can serve as a potential substitute for ANB and APDI. The new threedimensionally based landmarks and measurements are reliable, and there is great potential for future use of 3D analyses for diagnosis and research. (Angle Orthod. 2015;85:3-10.)