Objectives: The most typical maxillofacial feature of patients with acromegaly is mandibular protrusion. This study aimed to determine differences in maxillofacial morphology between skeletal Class III patients with and without acromegaly using cephalometric analysis. Methods: Cephalograms of 37 patients with acromegaly (Acro), 37 age-matched non-acromegalic patients with skeletal Class III malocclusion (C-III), and 37 age-matched Class I malocclusion patients (C-I; control) were retrospectively collected. The skeletal and dental morphology of each group was analyzed using cephalometric analysis, which included linear and angular measurements and facial profilograms. In addition, we analyzed diagnostic performance and cutoff values for discriminating acromegaly from skeletal Class III malocclusion using receiver operating characteristic (ROC) curve analysis. Results: The mandibular ramus height was larger in the Acro group than in the other groups. The increase in L1/MP in the Acro group, which represented labial inclination of the mandibular central incisors, was the most characteristic feature in this study. ROC curve analysis indicated that a cutoff value of 88.4° for L1/MP had the highest diagnostic performance in discriminating acromegaly from non-acromegalic Class III malocclusion. Conclusions: Acromegaly was characterized by a greater degree of bimaxillary prognathism than was non-acromegalic Class III malocclusion. Focusing on labial inclination of the mandibular central incisors would be the most useful way to differentiate acromegaly from non-acromegalic Class III malocclusion.