Methods of estimating arterial-venous O2 content difference, mixed venous CO2 content and tension, and average arterial CO2 content are presented. They are based on the continuous gas analysis of expired air during a prolonged expiration. The influence of CO2 storage in lung tissue and certain pathophysiologic conditions on the accuracy of these methods was systematically investigated with a comprehensive multi-chamber computer simulation of the lung. For normal levels of CO2 storage capacity, satisfactory estimates of arterial-venous O2 content difference are feasible for differences less than 8 volumes percent; with high levels of CO2 storage capacity, large errors can occur. Storage of CO2 in lung tissue causes large errors in the estimates of mixed venous CO2 content and tension, and average arterial CO2 content ; reliable estimates do not appear to be feasible from analysis of expired gas. Simulated pathophysiologic conditions of interstitial pulmonary edema or atelectasis also introduce large errors. This analysis delineates the theoretic limitations of an estimation technique in clinical applications where acute respiratory dysfunctions occur. © 1976.