Objective To assess the effect of high caloric loads on CO2 metabolism and ventilation. Design Retrospective, clinical review. Setting Intensive and special care units of a university medical center. Patients A consecutive series of 78 intubated patients who underwent 129 metabolic measurements as part of their nutritional support. Measurements and Main Results A total of 129 measurements of oxygen consumption, CO2 production, respiratory quotient, energy expenditure, minute ventilation, alveolar ventilation, deadspace ventilation, Paco2, respiratory rates and volumes, and substrate intake were made in 78 critically ill patients to determine their response to caloric loads. Statistically significant differences in indexed CO2 production, exhaled minute ventilation, deadspace ventilation, and intermittent mandatory ventilation rate existed between groups of patients with respiratory quotient of >1 or respiratory quotient of >1. Total caloric and carbohydrate caloric intake were 21% greater in those patients with respiratory quotient of >1, but this was not a statistically significant difference (p = .51). There was no significant difference between the groups for indexed oxygen consumption, alveolar ventilation, Paco2, or measured energy expenditure. There was a correlation between carbohydrate caloric intake and CO2 production for the entire population (r2 = .31, p < .001), with the latter relationship statistically greater (p = .006) in the respiratory quotient of >1 group (r2 = .76, p < .001) relative to the respiratory quotient of >1 group (r2 = .20, p < .001). There was a correlation between carbohydrate caloric intake and alveolar ventilation (r2 = .19, p < .001) with no significant difference between the two groups. A correlation between CO2 production and exhaled minute ventilation (r2 = .25, p < .001) was present only in the respiratory quotient of > group while a strong correlation between CO2 production and alveolar ventilation was observed for the entire population (r2 = .47, p < .001) with no difference between groups. Conclusions Increased CO2 production, exhaled minute ventilation, and deadspace ventilation values in the overfed group and the lack of difference between alveolar ventilation, Paco2, and measured energy expenditure, along with correlations between CO2 production and alveolar ventilation suggest that carbohydrate loads increase CO2 production which drives alveolar ventilation, thus preventing hypercapnia. When alveolar ventilation does not increase (and Paco2 increases) or when the spontaneous breathing rate increases to augment alveolar ventilation, the clinical response of increasing mechanical ventilation may increase deadspace ventilation. (Crit Care Med 1994; 22:796–802)