In this cephalometric investigation, we evaluated the correction of Class III malocclusion in subjects who had attained postpubertal skeletal maturity and considered whether treatment timing influenced favorable craniofacial modifications. All subjects (n = 50) were treated with an initial phase of rapid maxillary expansion and protraction facemask therapy, followed by a second phase of preadjusted edgewise therapy. The treated sample was divided into an early treated group (early mixed or late deciduous dentition, 33 subjects) and a late treated group (late mixed dentition, 17 subjects). Mean treatment duration times were 7 years 2 months for the early treatment group and 4 years 5 months for the late treatment group. The treated patients were matched to untreated controls (early control group, 14 subjects; late control group, 10 subjects) on the basis of race, sex, mean age at first observation, mean age at second observation, mean observation intervals, and type of malocclusion. A modified version of Johnston's pitchfork analysis, with additional angular and linear measures for mandibular size and shape and for vertical skeletal relationships, was performed. Analysis of variance was used to evaluate the difference in means for each cephalometric variable in the treated groups compared with the corresponding control groups. The findings showed that orthopedic treatment of Class III malocclusion was more effective when it was initiated at an early developmental phase of the dentition (early mixed or late deciduous) rather than during later stages with respect to untreated Class III control groups. Patients treated with rapid maxillary expansion and facemask therapy in the late mixed dentition, however, still benefited from the treatment, but to a lesser degree. Early treatment produced significant favorable postpubertal modifications in both maxillary and mandibular structures, whereas late treatment induced only a significant restriction of mandibular growth. Significant changes in mandibular size were associated with significant changes in mandibular shape only in early treated subjects. The main contribution to overall occlusal correction was related to skeletal modifications rather than dental changes in both early and late treated groups.