Background The accuracy of oxygen consumption measurement by indirect calorimeters is poorly validated in mechanically ventilated intensive care patients where multiple confounders exist. This study sought to compare the Medgraphics Ultima (MGU) and Deltatrac II (DTII) devices, and the Douglas bag (DB) technique in mechanically ventilated patients at rest. Methods Prospective comparison of oxygen consumption measurement using three indirect calorimetry techniques in stable, resting mechanically ventilated patients at rest. Oxygen consumption (VO2), carbon dioxide production (VCO2), resting energy expenditure (REE), and respiratory quotient (RQ) were recorded breath-by-breath by the MGU over a 30–75 min period. During this time, simultaneous measurements were taken using the DTII, the DB, or both. Results While there was no systematic error (bias) between measurements made by the three techniques (VO2: MGU vs DTII 3.6%, MGU vs DB 3.3%), the limits of agreement were wide (VO2: MGU vs DTII 33%, MGU vs DB 54%). Conclusions Resting oxygen consumption values in stable mechanically ventilated patients measured by the three techniques showed acceptable bias but poor precision. There is an important clinical and research need to develop new indirect calorimeters specifically tailored to measure oxygen consumption during mechanical ventilation.