Background: Partial rebreathing is a noninvasive method for measuring pulmonary blood flow (PBF). This study examines the systematic errors produced by the partial rebreathing technique utilizing a comprehensive mathematical model of the cardiorespiratory system of a healthy, 70-kg adult male. Methods: The model simulates tidal breathing through a branched respiratory tree and incorporates the effects on carbon dioxide dynamics of lung tissue mass, vascular transport delays, multiple body compartments, and realistic blood-gas dissociation curves. Four studies were performed: (1) errors produced under standard conditions, (2) effects of recirculation, (3) effects of alveolar-proximal airway partial pressure of carbon dioxide (Pco2) differences, and (4) effects of rebreathing time. Results: Systematic errors are less than 10% when the simulated PBF is between 3 and 6 l/min. At 2 l/min, PBF is overestimated by approximately 35%. At 14 l/min, PBF is underestimated by approximately 40%. At PBF of greater than 6 l/min, recirculation causes approximately 60% of the systematic error, alveolar-proximal airway differences cause approximately 20%, and alveolar-arterial differences cause approximately 20%. The standard rebreathing time of 50 s is shown to be excessive for PBF of greater than 6 l/min. At PBF of less than 3 l/min, errors are caused by inadequate rebreathing time and alveolar-arterial gradients. Conclusions: Systematic errors in partial rebreathing cardiac output measurements have multiple causes. Our simulations suggest that errors can be reduced by using a variable rebreathing time, which should be increased at low PBF so that quasiequilibrium in the alveoli can be achieved and decreased at high PBF to reduce the effects of recirculation.