Even though the clinical efficacy is not well established, theophylline is commonly prescribed as a second or third line drug after inhaled beta 2-agonists and corticosteroids for patients with chronic obstructive pulmonary disease (COPD). The therapeutic index is narrow, and therefore theophylline is often given in a "safe standard dose", e.g. 300 mg b.i.d. We studied the long-term effect of sustained-release theophylline 300 mg b.i.d. over four weeks in 48 patients with severe irreversible COPD (FEV1: 0.99 +/- 0.45 l, FVC: 2.21 +/- 0.68 l) in a randomized, double-blind crossover study. During theophylline treatment there was significant improvements in dyspnoea score (p < 0.001) and morning peak-flow (p < 0.05). In spite of this, there was no significant change in the patients' "sense of well-being" or their daily use of inhaled beta-agonist. Spirometric tests or arterial blood gas values did not change significantly either. It is concluded that addition of theophylline in a "safe standard dose" (i.e. 300 mg b.i.d.) has only limited value in these patients.