We compared the oxygen cost of breathing between pressure-support ventilation (PSV) and airway pressure release ventilation (APRV). This prospective, randomized, crossover study was conducted in a mixed ICU of a university hospital. Twenty clinically stable and spontaneously breathing patients after long-term mechanical ventilation were included. The patients were randomized to start on either PSV or APRV mode and measurements were obtained after an adaptation period of 30 minutes with a PaCO2 between 35-45 mmHg and PaO2 above 60 mmHg. Patients were then switched to the other mode and the same measurements were repeated. Indirect calorimetry was performed during each ventilatory mode for a period of 30 minutes. Oxygen consumption, energy expenditure, CO2 production, and respiratory quotient were measured. The parameters did not differ significantly between the two ventilatory modes, regardless of the patient's randomization. There were no statistically significant differences with regard to respiratory rate, minute volume, and blood gas analysis. All patients tolerated both ventilatory modes without signs of discomfort. PSV and APRV produced similar results in terms of oxygen cost of breathing and other metabolic variables.