Technologies for minimally-invasive cardiac output measurement in patients during surgery remain little used in routine practice. We tested a redeveloped system based on CO2 elimination (VCO2) by the lungs for use in ventilated patients, which can be seamlessly integrated into a modern anesthesia/monitoring platform, and provides automated, continuous breath-by-breath cardiac output monitoring. A prototype measurement system was constructed to measure VCO2 and end-tidal CO2 concentration with each breath. A baseline measurement of non-shunt cardiac output was made during a brief oscillating change in ventilator rate, according to the differential CO2 Fick approach and repeated at 5-10 min intervals. Continuous breath-by-breath monitoring of cardiac output was performed between these intervals from measurement of VCO2, using a derivation of the Fick equation applied to pulmonary CO2 elimination and cardiac output displayed in real time. Measurements were compared with simultaneous measurements by thermodilution in 50 patients undergoing cardiac surgery or liver transplantation. Overall mean bias [sd] for agreement in cardiac output measurement was - 0.3 [1.1] L/min, percentage error ± 38.7%, intraclass correlation coefficient = 0.91. Concordance in measurement of changes of at least 15% in cardiac output was 81.4%, with a mean angular bias of - 1.7°, and radial limits of agreement of ± 76.2° on polar plot analysis. The accuracy and precision compared favourably to other clinical techniques. The method is relatively seamless and automated and has potential for continuous, cardiac output monitoring in ventilated patients during anesthesia and critical care.