In nonintubated patients, metered-dose inhalers (MDIs) are accepted as the most convenient, efficient, and cost effective method of administering inhaled bronchodilators. Recent studies have demonstrated the efficacy of MDIs in ventilator-supported patients; however, the optimal dose of a bronchodilator from a MDI is unknown. We determined the response to increasing doses of albuterol administered by a MDI and cylindrical spacer to 12 mechanically ventilated patients with chronic obstructive pulmonary disease (COPD). Four, eight, and 16 puffs of albuterol were given at 15-min intervals. Rapid airway occlusion were performed before and at 5-min intervals after albuterol for 80 min. Respiratory mechanics were also measured for 60 min in another group of seven patients with COPD who received four puffs of albuterol. Significant decrease in airways resistance occurred after administration of albuterol (p < 0.001). The decrease in airway resistance with four puffs of albuterol was comparable to that observed with cumulative doses of 12 puffs (p = 0.12) and 28 puffs (p = 0.25). Heart rate increased significantly (p < 0.01) after a cumulative dose of 28 puffs. The decrease in airway resistance was sustained for 60 min in the group that received only four puffs of albuterol (p < 0.003). In conclusion, four puffs of albuterol given by a MDI and spacer provided the best combination of bronchodilator effect and safety in stable mechanically ventilated patients with COPD.