The aim of the present study was to compare the efficacy and the tolerability of salmeterol and theophylline in patients with nocturnal asthma. 16 patients were entered into a randomized, double-blind, crossover trial. Using a double-dummy technique, salmeterol (50 micrograms b.i.d. by MDI) or theophylline (Uniphyllin; 600 mg nocte orally) were given for periods of 7 days with a wash-out period of 7 days between treatment periods. With salmeterol the number of nights with an overnight fall in peak expiratory peak flow rate (PEFR) of at least 20% was reduced by about 20% compared to about 10% with theophyllin (p < 0.05 for the difference between salmeterol and theophylline). With respect to nocturnal symptoms 62.6% of the patients had rare or non symptoms without and 84.7% with salmeterol, compared to 46.5% without and 67.3% with theophylline (p < 0.05). With respect to the improvement of early morning symptoms, the increase of nights with none or rare symptoms was 46.2% with salmeterol compared to 25.8% with theophylline. The overall parameter of efficacy defined as a) the number of nights with an overnight fall in PEFR or less than 20% als well as b) none or rare nocturnal symptoms and c) none or rare early morning symptoms increased from 23.4% at baseline to 75.1% during treatment with salmeterol compared to an increase from 24.5% at baseline with 54.8% during treatment with theophylline (p < 0.05). 12 patients preferred salmeterol over theophylline (p < 0.05). 3 patients had gastrointestinal disturbances during theophylline treatment. It can be concluded that both salmeterol and theophylline are effective in the treatment of nocturnal asthma. With respect to the overall efficacy and the tolerability salmeterol is superior to theophylline.