The effects of reduced caloric intake on ventilatory drive were investigated in normal volunteers. During a ten-day semistarvation period, six subjects (group 1) received parenterally an amino acid solution providing 550 kcal/d sufficient to prevent a negative nitrogen balance. Six subjects (group 2) received in addition a safflower oil solution providing a total caloric intake of 1,100 kcal/d. Hypoxic ventilatory drive was estimated by an index (parameter A) of the relation between minute ventilation (VE) and hypoxia. In group 1, mean values (+/- SEM) of A decreased significantly from 161.5 (+/- 42.0) to 48.9 (+/- 12.0) by day 10 (p less than 0.05), indicating a severe depression of hypoxic drive despite a positive nitrogen balance. In group 2, A did not change significantly (p greater than 0.05) from control values indicating a preserved hypoxic ventilatory drive. In both groups, the slopes of the line relating VE to arterial PCO2 (delta VE/delta PaCO2) did not change significantly during the ten-day semistarvation period consistent with preservation of the hypercapnic ventilatory drive. These data indicate that during periods of starvation, parenteral administration of aminoacids in an amount sufficient to maintain nitrogen balance is inadequate to prevent depression of respiratory control mechanisms unless a minimum daily caloric intake is achieved.