We wanted to know wheter the paradoxical response to CO2 under various background concentrations of O2 in preterm infants was mediated at the peripheral chemoreceptors. In five preterm infants we estimated peripheral chemoreceptor activity using the immediate change in ventilation (first 30 s) when 15%, 40%, 60%, or 100% O2 was substituted for 21% O2. Potentiation between O2 and CO2 was assessed by comparing the response with and without 4% CO2. CO2 enhanced the immediate hyperventilation with hypoxia (P less than 0.005) and reduced the immediate hypoventilation with hyperoxia (P less than 0.025 for 40% O2). This effect of CO2 increased from .00% to 15% O2 (P less than 0.05). These findings suggest: 1) CO2 interacts with O2 at the peripheral chemoreceptor level, and 2) because this interaction is more pronounced with hypoxia, the flatter CO2 response we observed with hypoxia was probably not mediated through the peripheral chemoreceptors and is likely to be central in origin.