Concern about side-effects of theophylline prompted us to investigate whether this drug could be eliminated from the multi-medication regimen of severe asthmatics. We studied patients with a demonstrated requirement for systemic steroids who were taking most other available anti-asthma medications in an attempt to reduce systemic steroids while maintaining clinical stability. Five in-patients, 12-15 years old, completed a double-blind, cross-over trial of theophylline vs placebo. All were stable for 4 weeks prior to the study with normal spirometry and mildly elevated lung volumes. Regular medications consisted of long-acting theophylline with levels between 12 mcg/ml and 16 mcg/ml, and prednisone 10-30 mg on alternate days. In addition, they were all taking inhaled metaproterenol, cromolyn sodium, atropine sulphate, and beclomethasone dipropionate four times daily (qid). Patients received either theophylline or placebo during two drug periods. All other medications were unchanged. Parameters measured were symptom score, number of extra respiratory treatments (prn RTs), increase in steroid dosage, and daily spirometry. During the placebo period, all five patients required increased steroids, daily spirometry decreased and three patients developed severe exacerbations unrelated to viral infection. A marked increase in symptom score occurred within 48 hr of discontinuing theophylline in all. These findings emphasize that theophylline is beneficial in a subset of severe asthmatics who cannot be controlled with all other available bronchodilators, cromolyn, and inhaled and systemic steroids.