Maxillary deficiency is one of the facial features of Down syndrome (DS). Differences in craniofacial morphology between DS and nonsyndromic skeletal Class III malocclusion with maxillary deficiency remain unclear. This study compared the craniofacial differences of white male children from Central-Western Brazil with DS (n = 30, mean age: 8 years 3 months), skeletal Class III profile with maxillary deficiency (n = 30, mean age: 7 years 9 months), and skeletal Class I profile (n = 30, mean age: 8 years 2 months), using lateral cephalometric radiographs. The differences among the three groups were compared with analysis of variance and Tukey's tests. The DS group showed reduced anterior cranial base (S-N, P < 0.001] and facial dimensions (Co-Gn, N-Me, N-ANS, and ANS-Me, P < 0.001), except in posterior dimensions (S-Go, P < 0.005; Ar-Go, P > 0.005). Maxillary length (Co-A, P < 0.001) and facial convexity (NAP, P < 0.005) were reduced when compared with the control group, although maxillary position to cranial base (SNA, P < 0.005) was within the normal range. A flattened cranial base (BaSN, P < 0.001) also contributed to differentiating DS from nonsyndromic groups. The group with maxillary deficiency showed a more unfavourable maxillomandibular relationship (MMD, P < 0.001) and a mandibular protrusion (SNB, P < 0.001). Subjects with DS differed from Class III with maxillary deficiency with respect to the flatter cranial base and reduced maxillary length. Maxillary deficiency was not so expressive in the face of DS subjects because of the overall reduction in craniofacial dimensions.