We compared the effect of salbutamol and placebo in a double-blind study of preterm infants with bronchopulmonary dysplasia, using a randomized, crossover design with several replicates per subject. Sixty-two tests were performed on 20 ventilator-dependent infants weighing less than 1500 gm. Patients were entered as early as the first week of life and studied for at least 4 weeks or until extubation. Each subject was his own control subject and was randomly assigned to a placebo-salbutamol or salbutamol-placebo sequence administered on 2 consecutive days of each week. Static compliance, expiratory resistance of the respiratory system, and changes in transcutaneous oxygen and carbon dioxide tension were measured. Static compliance improved by 0.240 ml/cm H2O/kg (35.3%) after salbutamol and by 0.010 ml/cm H2O/kg (2.8%) after placebo (p less than 0.0001). The presence of a predetermined decrease in carbon dioxide tension correlated with large changes in static compliance per kilogram and with the need for a high level of fractional inspired oxygen. The magnitude of the clinical and physiologic improvement observed, and the early response suggest that long-term bronchodilator therapy starting as early as the second week of life may be beneficial for very low birth weight infants with early bronchopulmonary dysplasia.