STUDY OBJECTIVES: Although hypercapnia and/or hypoxia are frequently present during chronic lung disease of infancy and have also been implicated in sudden infant death syndrome (SIDS), their effect on cardiac autonomic regulation remains unclear. The authors' goal is to test that hypercapnia and hypoxia alter sleep-wake cycle-dependent heart rate variability (HRV) in the neonatal period. DESIGN: Experimental study measuring HRV during sleep states in lambs randomly exposed to hypercapnia, hypoxia, or air. SETTING: University center for perinatal research in ovines (Sherbrooke, Canada). INSERM-university research unit for signal processing (Rennes, France). PARTICIPANTS: Six nonsedated, full-term lambs. INTERVENTIONS: Each lamb underwent polysomnographic recordings while in a chamber flowed with either air or 21% O(2) + 5% CO(2) (hypercapnia) or 10% O(2) + 0% CO(2) (hypoxia) on day 3, 4, and 5 of postnatal age. MEASUREMENTS AND RESULTS: Hypercapnia increased the time spent in wakefulness and hypoxia the time spent in quiet sleep (QS). The state of alertness was the major determinant of HRV characterized with linear or nonlinear methods. Compared with QS, active sleep (AS) was associated with an overall increase in HRV magnitude and short-term self-similarity and a decrease in entropy of cardiac cycle length in air. This AS-related HRV pattern persisted in hypercapnia and was even more pronounced in hypoxia. CONCLUSION: Enhancement of AS-related sympathovagal coactivation in hypoxia, together with increased heart rate regularity, may be evidence that AS + hypoxia represent a particularly vulnerable state in early life. This should be kept in mind when deciding the optimal arterial oxygenation target in newborns and when investigating the potential involvement of hypoxia in SIDS pathogenesis.