Objective: To (1) document the prevalence and patterns of hypodontia (permanent tooth agenesis) in Down syndrome (DS) and (2) explore whether maxillary or mandibular hypodontia or simultaneous agenesis of all third molars was associated with differential alterations of the craniofacial morphology. Materials and Methods: Longitudinal panoramic radiographs of 25 white patients with DS (12 male, 13 female; mean age, 15.1 years) treated at The Hospital for Sick Children, Toronto, Ontario, Canada, were evaluated to document hypodontia. Cephalometric measurements of subjects with maxillary or mandibular hypodontia or agenesis of all third molars were compared with those of subjects without hypodontia in these regions using analysis of covariance adjusted for age, gender, and proportion of other missing teeth in the total number of missing teeth. Results: Hypodontia was seen in 92% of the sample when third molars were considered and in 56% when third molars were not considered. Hypodontia was more prevalent and severe in females. The most frequently agenetic teeth were maxillary and mandibular third molars . maxillary lateral incisors . mandibular second premolars . mandibular incisors . maxillary second premolars . maxillary second molars. Simultaneous agenesis of all third molars was seen in 52% of the sample. Maxillary hypodontia was not associated with significant regional craniofacial differences, while mandibular hypodontia was associated with decreased mandibular length and increased ramus:body ratio. Agenesis of all third molars was not associated with significant craniofacial differences. Conclusions: Hypodontia is widely prevalent in DS. The effect of the syndrome appears to be stronger than that of regional hypodontia in differentially altering the craniofacial morphology. (Angle Orthod. 2011;81:260-269.)