Introduction The objectives of this study were to clarify the characteristics of cranial-base morphology in adults with skeletal Class III malocclusion and investigate factors relating to the establishment of a skeletal Class III malocclusion. Methods Initial lateral cephalograms of women were examined. Subjects with an ANB angle of 0° to 4°, normal overjet and overbite, and a Class I molar relationship were classified as Class I (n = 86). Those with an ANB angle less than −1°, a Wits appraisal less than 2 mm, a negative overjet, and a Class III molar relationship were the Class III group (n = 86) in this study. Angular, linear, and coordinate measurements were made. Multivariate analysis of variance and the Student t test were used to analyze significant differences between the 2 groups. Discriminant analysis, logistic regression analysis, and decision analysis were used to identify which cranial-base and maxillomandibular variables influenced the establishment of a skeletal Class III malocclusion. Results The Class III group had smaller values for NSBa, SeSBa, FH-SSe, and FH-SBa. Sphenoidale and basion were more inferior and anterior than those of the Class I group. There was no difference in the anterior and posterior cranial-base lengths between the groups. Greater mandibular length was the first major characteristic in the Class III group, followed by smaller values for SeSBa and NSBa. Conclusions Cranial-base morphology in adults with a skeletal Class III malocclusion is different from that in a skeletal Class I malocclusion. Smaller cranial-base angles, steeper posterior cranial bases, more inferiorly positioned sphenoidale, and more anteriorly positioned basion are major characteristics of skeletal Class III malocclusions. These characteristics play important roles in the establishment of a skeletal Class III malocclusion.