Peak oxygen consumption (VO2) is a powerful prognostic predictor of survival in patients with heart failure (HF) because it provides an indirect assessment of a patient's ability to increase cardiac output (CO). However, many peripheral factors affect VO2. Inert gas rebreathing using low-concentration soluble and insoluble inert gases can derive CO by the Fick principle. The Innocor rebreathing system uses an oxygen-enriched mixture of an inert soluble gas (0.5% nitrous oxide) and an inert insoluble gas (0.1% sulfur hexafluoride) measured by photoacoustic analyzers over a 5-breath interval. The practicality of this device in measuring CO and VO2 during exercise was assessed in patients with HF. Ninety-two consecutive exercise tests were prospectively performed in 88 patients with HF using the Innocor system. Incremental bicycle exercise was performed with CO measurements at rest, at 50 W, and at peak exercise. The mean age of the 68 men and 20 women was 54 ± 13 years; 33% had coronary artery disease, and 67% had dilated cardiomyopathy. The mean left ventricular ejection fraction was 24 ± 9%. Patients were able to rapidly learn the rebreathing technique and easily integrate it into the exercise protocol. Eighty-six percent of the tests had successful measurement of metabolic and cardiac output data. Mean CO at rest was 3.5 ± 1.1 L/min and increased to 7.2 ± 2.7 L/min. Mean peak VO2 was 12.6 ± 4.7 ml/kg/min. A significant linear correlation was observed between peak VO2 and peak CO (r = 0.64, p <0.0001). In conclusion, combined metabolic stress testing with inert gas rebreathing can be easily performed in patients with HF.