The use of theophylline in patients with "irreversible" chronic obstructive pulmonary disease is controversial. Possible favorable actions of theophylline, including improved mucociliary clearance, stimulation of respiratory drive, enhanced cardiovascular function, and increased diaphragmatic contractility and endurance, have either been shown to be minor in degree, or have not been demonstrated in patients with irreversible chronic obstructive pulmonary disease. No well-designed trial has yet shown improved exercise capacity following theophylline treatment in these patients. Nevertheless, considering that some patients benefit symptomatically in the absence of objective improvement, a cautious trial of theophylline appears indicated in patients with severe irreversible chronic obstructive pulmonary disease, with discontinuation if there is no objective or subjective improvement. Theophylline therapy should be initiated via the intravenous route during acute exacerbations, but otherwise should start with sustained-release oral preparations of anhydrous theophylline. Oral therapy should begin at low doses in stable patients to avoid side effects, and dosing should take into account the many factors, such as age, cardiovascular and liver function, smoking status, and possible drug interactions, that can affect theophylline metabolism.