The ability to assess cardiac output (Q(T)) noninvasively has been the focus of interest for many researchers. While the open-circuit acetylene (C2H2) method seems promising, it is prone to error due to ventilation-perfusion (V/Q) inequality. Measurements during exercise, at high altitude or in patients with chronic obstructive pulmonary disease (COPD) could be unreliable and further validation studies under these circumstances may be needed. We used a computer model based on formulae derived from the multiple inert gas elimination technique to quantify error in Q(T) measurements resulting from V/Q inequality at rest, during exercise or at high altitude. Moreover, potential errors encountered in patients with COPD were quantified. In healthy subjects, V/Q inequality related measurement error seems negligible, under both normoxic and hypoxic conditions and especially during exercise. In COPD, errors up to 20% at rest and up to 15% during exercise are expected. It is therefore concluded from our model that the open-circuit C2H2 uptake method is expected to be accurate in normal subjects. Its validity in COPD needs further study.