Introduction: The objective of this study was to evaluate and compare the 3-dimensional (3D) aging changes of the lips among adult skeletal Class I, II, and III malocclusion. Methods: Female adult orthodontic patients aged 20-50 years with pretreatment cone-beam computed tomography scans were retrospectively classified according to age (20s [20-29 years], 30s [30-39 years], and 40s [40-49 years]) and then subclassified by malocclusion into skeletal Class I, II, and III relationship (9 groups; n 5 30 per group). Positional differences in midsagittal and parasagittal soft-tissue landmarks and 3D morphologic aging changes of the lips were evaluated using cone-beam computed tomography scans. Results: Labiale superius and cheilion for patients in their 40s indicated a significant downward and backward position compared with those in their 20s, regardless of skeletal classifications (P <0.05). Accordingly, the upper lip height decreased, and the mouth width increased significantly (P <0.05). For Class III malocclusion, the upper lip vermilion angle was greater for patients in their 40s than those in their 20s (P <0.05), whereas the lower lip vermilion angle was only lower for patients with Class II malocclusion (P <0.05). Conclusions: Middle-aged adult females (40-49 years) had a lower upper lip height and greater mouth width than those in their 20s, regardless of skeletal malocclusion. However, prominent morphologic aging changes of the lips were noted on the upper lip for skeletal Class III malocclusion and the lower lip for skeletal Class II malocclusion, implying that the underlying skeletal features (or malocclusion) may influence 3D aging changes of the lips. (Am J Orthod Dentofacial Orthop 2023;164:516-29)