A higher incidence of fatal asthma after increased use of combined inhaled beta 2-agonists and theophylline has been attributed to additive cardiac toxicity of these agents. This study had three major objectives: first, to evaluate the efficacy and safety of a new long-acting beta 2-agonist, bitolterol mesylate, given as metered-dose aerosol in a regular "round-the-clock" asthma medication regimen; second, to compare the efficacy and safety of bitolterol with those of sustained-release theophylline alone and of the combination of bitolterol and theophylline; third, to use 24 hr Holter monitoring to evaluate cardiac toxicity of the three medication regimens. This was a 6 wk double-blind study of regular, daily medication in 36 young non-steroid-dependent and 37 older steroid-dependent stable asthmatic patients. All patients had two 24 hr Holter ECG monitorings during the 2 wk baseline period when all patients received theophylline only and four further 24 hr Holter monitorings during the double-blind period. All Holter recordings from the study groups showed no significant abnormalities in any treatment group. Pulmonary function studies were performed on 4 study days in the 6 wk double-blind period. The largest increase in bronchodilator effect was obtained with combined medication and the smallest with theophylline alone. Mean duration of action was markedly longer in the combined treatment group (greater than 7 hr) than with bitolterol mesylate aerosol or theophylline alone (greater than 5 and greater than 4 hr, respectively) in the non-steroid-dependent patients. Degree of bronchodilation and duration of action was less in the steroid-dependent patients in all treatment groups. There is no evidence from cardiac monitoring that therapeutic doses of bitolterol mesylate or theophylline alone or in combination have cardiotoxic effects.