The effectiveness and safety of individualized theophylline doses administered as such and in combination with ephedrine and hydroxyzine was investigated in 23 children with chronic asthma who received these medications and a placebo for 1 week each, double-blind and in randomized sequence. Theophylline, determined by prior clinical titration in each patient, averaged 7.3 mg/kg per dose administered every 6 hr, with peak serum theophylline concentrations averaging about 16 mug/ml. Asthmatic symptoms were controlled with theophylline. Ephedrine, alone or in combination, was relatively ineffectual in these patients. None of the drugs given alone was associated with significant adverse effects but both ephedrine-theophylline combinations (with and without hydroxyzine) were associated with insomnia, nervousness, and gastrointestinal complaints. Since the combinations were not significantly more effective than theophylline alone, the apparent toxicity of these combinations suggests a contraindication for the routine use of ephedrine with theophylline in the management of chronic asthma.