We examined theophylline pharmacokinetics for changes caused by the addition of erythromycin in patients with chronic bronchitis and obstructive pulmonary disease. Twelve hospitalized patients were randomized in a crossover fashion to receive aminophylline and either erythromycin or placebo. After the eighth dose, plasma was analyzed for theophylline, using the enzyme-mediated immunoassay technique. A 6-h urine collection was analyzed for theophylline metabolites, using high-pressure liquid chromatography. Erythromycin significantly decreased mean theophylline clearance by 22% from 4.9 L/min to 3.87 L/min (p less than 0.05). Mean peak theophylline levels increased 28% from 11.9 micrograms/ml to 15.3 micrograms/ml (p = 0.05). No change in urine theophylline metabolites was found. Patients with chronic bronchitis and obstructive pulmonary disease who begin erythromycin while receiving a preexisting therapeutic theophylline regimen experience a significant elevation of theophylline concentration, which predisposes to theophylline toxicity. For those patients with theophylline levels at the higher end of the therapeutic range (15 to 20 micrograms/ml), we recommend an initial 25% reduction in theophylline dosage when erythromycin is added. Serum theophylline levels should be monitored for further refinement of dosage.