Rationale: Improvement in forced expired volume in one second (FEV1) is a main endpoint in clinical trials assessing the efficacy of bronchodilators. However, the effect of bronchodilators on maximal expiratory flow may be confounded by thoracic gas compression (TGC). Objective: To determine whether thoracic gas compression confounds effect of albuterol on FEV1. Methods: We evaluated the response to albuterol inhalation in ten healthy, nine asthma and fifteen COPD subjects with mean (SD) age in years of 38 (11), 45 (11), and 64 (8) respectively. Lung mechanics were measured at baseline and 20 minutes after inhalation of 180 micrograms of albuterol. We then applied a novel method to calculate FEV1 corrected for the effect of TGC (NFEV1). Results: Prior to albuterol administration, NFEV1 was significantly higher than FEV1. However, post-albuterol inhalation, FEV1 increased more than NFEV1 because of reduced TGC. In multiple regression analysis, the changes in TGC, inspiratory lung resistance and ratio of residual volume to total lung capacity post-albuterol, predicted more than 75% of FEV1 improvement in COPD patients. Conclusion: Improvements in FEV1 following albuterol in patients with COPD are due to reduction of lung resistance, hyperinflation and thoracic gas compression. The latter is negligible during tidal breathing. Thus, although reduction of lung resistance and hyperinflation may result in improved dyspnea with a bronchodilator, the contribution of TGC reduction to improvement of FEV1 may not exert any meaningful clinical effect during tidal breathing. This fact has to be taken in consideration when assessing the efficacy of new bronchodilators.