During routine monitoring of hospitalized children with asthma receiving a sustained-release theophylline formulation, we frequently observe unpredictable fluctuations in serum theophylline concentration (STC). We evaluated eight asthmatic patients (ages 4 to 17 years) with inconsistent STCs to determine the cause of this phenomenon. Only minimal variation in STC and therefore theophylline clearance was noted during a 24-hour period of continuous intravenous aminophylline infusion. However, marked variability in STC was observed when measured every 2 hours for 48 hours after 6 days of continuous therapy orally. In addition, the time required to reach peak and trough STCs varied from dose to dose. Inasmuch as clearance was shown to be constant, the variability was attributed to inconsistent theophylline absorption. Unpredictable fluctuations of STC secondary to variable absorption from this sustained-release theophylline preparation may occur in certain patients. Appreciation of this potential variability is necessary for the proper interpretation of STC measurements and subsequent dosage adjustment.