Background and Aims: The 2 currently available indirect calorimeters, CCM Express Indirect Calorimeter (MedGraphics, St Paul, MN) and Quark RMR ICU Indirect Calorimeter (COSMED, Rome, Italy), have not been validated against a gold standard in mechanically ventilated patients. Our aim was to do so using a gold-standard, modified Tissot bell-spirometer method in mechanically ventilated patients who were hemodynamically, respiratory, and metabolically stable. Methods: We studied 30 patients undergoing general anesthesia and major gynecological surgery. We measured oxygen consumption ((Formula presented.) O₂) and resting energy expenditure (REE) in a randomized, sequential, crossover design with double determination of each device. Results: Compared with the modified Tissot bell-spirometer, the CCM Express Indirect Calorimeter demonstrated a mean Δ-REE of +361 kcal/d, corresponding to a 31% overestimation of energy requirements. Bland-Altman analysis for REE showed a mean (SD) bias of 384 (124) with limits of agreement 142–627 kcal/d. QUARK RMR ICU demonstrated a mean Δ-REE of 81 kcal/d, corresponding to a 7% overestimation of energy requirements. Bland-Altman plot analysis showed a mean (SD) bias of 77 (167) with limits of agreement −249 to 404 kcal/d. Conclusions: The QUARK RMR ICU Indirect Calorimeter compared better with the gold standard for values of (Formula presented.) O₂ and REE than did the CCM Express Indirect Calorimeter in mechanically ventilated patients who were circulatory and respiratory stable. Both indirect calorimeters had low precision.