Sleep disordered breathing (SDB) occurs at an increased incidence in children with Down Syndrome (DS) compared to the general pediatric population. We hypothesized that, compared with typically developing (TD) children with SDB, children with DS have a reduced cardiovascular response with delayed reoxygenation after obstructive respiratory events, and reduced sympathetic drive, providing a potential explanation for their increased risk of pulmonary hypertension. DESIGN: Beat-by-beat heart rate (HR) was analyzed over the course of obstructive events (pre, early, late, post-event) and compared between groups. Also compared were the time for oxygen resaturation post-event and overnight urinary catecholamines. SETTING: Pediatric sleep laboratory. PATIENTS: Sixty-four children aged 2-17 y referred for investigation of SDB (32 DS; 32 TD) matched for age and obstructive apnea/hypopnea index. MEASUREMENT AND RESULTS: Children underwent overnight polysomnography with overnight urine collection. Compared to TD children, those with DS had significantly reduced HR changes post-event during NREM (DS: 21.4 +/- 1.8 , TD: 26.6 +/- 1.6 , change from late to post-event, P <0.05). The time to resaturation post-event was significantly increased in the DS group (P <0.05 for both NREM and REM sleep). Children with DS had significantly reduced overnight urinary noradrenaline (P <0.01), adrenaline (P <0.05) and dopamine levels (P <0.01) compared with TD children. CONCLUSION: Children with DS and SDB exhibit a compromised acute cardio-respiratory response and dampened sympathetic response to SDB compared with TD children with SDB. These data may reflect autonomic dysfunction in children with DS that may place them at increased risk for cardiovascular complications such as pulmonary hypertension.