Objectives: This study identified the difference in energy expenditure and substrate utilization of patients during and upon liberation from mechanical ventilation. Methods: Patients under intensive care who were diagnosed with septic shock and dependent on mechanical ventilation were recruited. Indirect calorimetry measurements were performed during and upon liberation from mechanical ventilation. Results: Thirty-five patients were recruited (20 men and 15 women; mean age, 69 ± 10 years). Measured energy expenditures during ventilation and upon liberation were 2090 ± 489 kcal·d−1 and 1910 ± 579 kcal·d−1, respectively (P < .05). Energy intake was provided at 1148 ± 495 kcal·d−1 and differed significantly from all measured energy expenditures (P < .05). Mean carbohydrate utilization was 0.19 ± 0.1 g·min−1 when patients were on mechanical ventilation compared with 0.15 ± 0.09 g·min−1 upon liberation (P < .05). Mean lipid oxidation was 0.08 ± 0.05 g·min−1 during and 0.09 ± 0.07 g·min−1 upon liberation from mechanical ventilation (P > .05). Conclusions: Measured energy expenditure was higher during than upon liberation from mechanical ventilation. This could be the increase in work of breathing from the continuous positive pressure support, repeated weaning cycles from mechanical ventilation, and/or the asynchronization between patients’ respiration and ventilator support. Future studies should examine whether more appropriately matching energy expenditure with energy intake would promote positive health outcomes.