A randomized, double-blind, placebo-controlled clinical trial was designed to assess the safety, efficacy, and duration of the bronchodilation resulting from the addition of 500 μg of ipratropium bromide (Atrovent; Boehringer Ingelheim, CT) inhalation solution to standard small volume nebulizer treatments with 2.5 mg albuterol inhalation solution. A total of 195 patients (63% men, average age 64 years) with >10 pack-year smoking histories and stable, moderate-to-severe chronic obstructive pulmonary disease (COPD; forced expiratory volume in 1 second [FEV₁] 1.02 liter, 38.8% predicted) from eight university-affiliated chest clinics in seven U.S. cities were enrolled into the study. Asthma, rhinitis, and eosinophilia were exclusions, as was daily use of >10 mg of prednisone (or 20 mg on alternate days). There was a 2-week stabilization period during which the patients were instructed in the use of the small volume nebulizers, which they used three times daily with albuterol alone. They were asked to keep daily logs of peak flow rates, pulmonary symptoms, and additional medication usage. On their test day 1 the subjects came to the pulmonary function laboratory having been off theophylline for 24 hours and β₂-agonists for 12 hours and performed a baseline spirometry. They then received their morning small volume nebulizer treatment of albuterol to which was added either 500 μg of ipratropium bromide or a saline placebo. Spirometry was repeated at 15, 30, and 60 minutes, and then hourly for 8 hours. Subjects then took home a 2-week supply of albuterol and test drug for thrice daily use in their small volume nebulizer. They were evaluated for pulmonary symptoms and adverse effects every 14 days. The 8-hour spirometry was repeated on test day 43 and finally on test day 85. Primary data evaluated were the peak increase in FEV, and the area between the FEV₁ baseline value and the 8-hour FEV₁ curve. Similar calculations were made for forced vital capacity (FVC) and 25–75% forced expiratory flow (FEF_25–75%). On test day 1 the peak increase in FEV₁ for the ipratropium bromide+albuterol subjects was 26% greater than those on placebo+albuterol (p <0.003). The area under the 8-hour FEV₁ curve was 64% greater in those given ipratropium bromide on test day 1 (p <0.0002). Similar increases were seen in FVC and FEF_25–75%. The peak improvements in FEV_l and FVC with the addition of ipratropium bromide to albuterol were maintained on test days 43 and 85. Considering the safety and efficacy profiles of this combination, the data would suggest that ipratropium bromide inhalation solution should be considered first-line therapy for those patients with COPD requiring small volume nebulizer treatments.