We conducted a trial of inhaled salbutamol and orally administered theophylline in patients whose acute response to inhaled salbutamol was less than 25% of their baseline FEV1. Patients underwent 4 treatment periods, each of 2 wk duration, during which they received the following combinations: placebo-placebo, placebo-salbutamol, placebo-theophylline, and salbutamol-theophylline. The 19 patient who completed the study were all males with a mean age of 65 +/- 7.4 yr, mean FEV1 of 1.02 +/- 0.38, and mean VC of 2.73 +/- 0.19. Outcomes included twice-daily recordings of peak flow rates, spirometry, the distance patients could walk in 6 min, and clinical symptoms of dyspnea, fatigue, and emotional function. Clinically important and statistically significant differences between the 4 periods were noted on both physiologic and functional outcomes. For the group as a whole, improvement with inhaled salbutamol and orally administered theophylline was comparable, and additional benefit was gained from a combination of the 2 drugs. We conclude that both inhaled salbutamol and orally administered theophylline can improve airflow obstruction, functional exercise capacity, and quality of life in patients with primarily fixed air-flow limitation.