Hypoxia depresses ventilation in preterm infants. Because PACO2 does not rise, the decrease in ventilation has been attributed to a decrease in metabolism rather than to the central depressant effect of hypoxia. To determine whether central depression is present, we measured the ventilatory sensitivity to CO2 at varying inspired O2 concentrations in preterm infants. Eight babies (B.W.I to 2 kg;G.A.<36 weeks) were studied 10 times during the first 10 days of life. After breathing 21% O2 for 3 minutes, they were given 15,21,40 or 100% O2 for 4 minutes and then 2% CO2 plus the various concentrations of O2 for 4 minutes each. We determined respiratory minute volume and frequency, PACO2, PAO2 and heart rate. Ventilation was measured with a nosepiece and screen flowmeter, using a constant flow-through to eliminate dead space and valves. We plotted minute ventilation against PACO2 to assess the respiratory sensitivity at varying inspired O2 concentrations. The mean slopes of the CO2 response curves were 0.011, 0.022, 0.039 and 0.168 L/min/kg/mm Hg PACO2 with 15,21,40 and 100% inspired O2 respectively (p<0.05). Therefore, the more hypoxic the infant, the flatter was the response to CO2. These findings suggest: a)the respiratory center is depressed during hypoxia in preterm infants despite a decrease in PACO2; b) the response to inhaled CO2 is the opposite to that seen in male adults, where the higher the inspired O2 concentration, the flatter the response.