Objective : To perform a retrospective study to evaluate the effect of oral appliances, aimed at increasing the pharyngeal space, on obstructive sleep apnea (OSA) in infants with trisomy 21 (TS21). Design and Setting : Retrospective study in a tertiary referral center. Intervention : We analyzed data from 51 consecutive infants (mean age, 2.7 months) who underwent polysomnography (PSG) and were offered our treatment concept. Primary study variable was the mixed-obstructive apnea index (MOAI); OSA was defined as a MOAI ≥ 1. Results : Twenty-seven infants (53%) had OSA. Their median MOAI improved from 2.3 (1 to 13) to 0 (0 to 0.2; P < .05). Seven of these infants were treated with an appliance that included some type of velar extension to move the tongue base forward. Of the 24 infants without OSA at admission, follow-up PSG results were available for 13. Three infants from this group had developed OSA by the time of a repeat PSG. Conclusion : In patients with TS21, OSA may already develop in infancy. Early treatment may improve OSA. Oral appliances with some type of velar extension may be considered as an alternative to other treatment procedures.