Arousal and cardio-respiratory responses to respiratory stimuli during sleep are important protective mechanisms that rapidly become depressed in the active sleep state when episodes of hypoxia or asphyxia are repeated: whether responses to repeated hypercapnia are similarly depressed is not known. This study aimed to determine if arousal and cardio-respiratory responses also become depressed with repeated episodes of hypercapnia during sleep and whether responses differ in active sleep and quiet sleep. Eight newborn lambs were instrumented to record sleep state and cardio-respiratory variables. Lambs were subjected to two successive 12 h sleep recordings, assigned as either sequential control and test days, or test and control days performed between 12.00 and 00.00 h. The control day was a baseline study in which the lambs breathed air to determine spontaneous arousal probability. During the test day, lambs were exposed to a 60 s episode of normoxic hypercapnia (Fractional inspired CO2(F)= 0.08 and Fractional inspired O2(F)= 0.21 in N2) during every quiet sleep and active sleep epoch. The probability of lambs arousing during the hypercapnic exposure exceeded the probability of spontaneous arousal during quiet sleep (58%versus 21%, χ2= 54.0, P < 0.001) and active sleep (39%versus 20%, χ2= 10.0, P < 0.01), though the response was less in active sleep. Exposure to hypercapnia also resulted in a significant increase in ventilation in quiet sleep (150 ± 22%) and active sleep (97 ± 23%, P < 0.05), though the increase was smaller in active sleep (P < 0.05). Small (< 5%) blood pressure increases and heart rate decreases were evident during hypercapnia in quiet sleep, but not in active sleep. Arousal and cardio-respiratory responses persisted with repetition of the hypercapnic exposure. In summary, although arousal and cardio-respiratory responses to hypercapnia are less in active sleep compared with quiet sleep, these protective responses are not diminished with repeated exposure to hypercapnia.