Background The prone sleeping position, particularly in prematurely born infants, is associated with an increased risk of sudden infant death syndrome. A possible mechanism is an impaired ability to respond to respiratory compromise. The hypothesis that the ventilatory response to a carbon dioxide (CO2) challenge in convalescent, prematurely born infants would be lower in the prone compared with the supine position was therefore tested. Methods In each position, ventilatory responses to increasing levels of inspired CO2 were assessed. The airway pressure change after the first 100 ms of an occluded inspiration (P-0.1) and the maximum inspiratory pressure with an occluded airway during crying (P-imax) were measured; the ratio of the P-0.1 to the P-imax at each inspired CO2 level and the slope of the P-0.1/P-imax response were calculated. Chest and abdominal wall asynchrony was assessed using inductance plethysmography and functional residual capacity (FRC) measured using a helium gas dilution technique. Results Eighteen infants with a median postmenstrual age of 35 (range 35-37) weeks were studied. In the prone versus the supine position, the mean P-0.1 (p=0.002), the mean P-imax (p=0.006), the increase in P-0.1 with increasing CO2 (p=0.007) and the P-0.1/P-imax response slope (p=0.007) were smaller. Thoracoabdominal asynchrony was not significantly influenced by position or inspired CO2. FRC was higher in the prone position (p=0.019). Conclusions Convalescent, prematurely born infants have a reduced ventilatory response to CO2 challenge in the prone position, suggesting they may have an impaired ability to respond to respiratory compromise in that position.