The effect of total parenteral nutrition (TPN) induced cholestasis on theophylline clearance was examined in premature neonates. Thirty-six neonates receiving TPN and theophylline concurrently were reviewed. Aminophylline was administered according to a standard protocol of 6 mg/kg loading dose, followed by a maintenance dose of 2.5-5 mg/kg every 12 h. Of the 36 neonates reviewed, 18 developed cholestasis (direct bilirubin greater than or equal to 1 mg/100 ml and direct bilirubin greater than or equal to 60% of total bilirubin). The remaining 18 did not develop cholestasis. The two groups were closely matched for gestational age, 5-min apgar score, and sex. The neonates with cholestasis had a mean maximum direct bilirubin of 5.19 mg/100 ml (range 1-13.8 mg/100 ml) as compared to the patients without cholestasis who had a mean maximum direct bilirubin of 0.54 mg/100 ml (range 0.3-0.8 mg/100 ml). Steady-state theophylline clearance was determined at least once a week for at least 4 separate weeks. The study lasted a minimum of 8 weeks, and if more than one theophylline clearance was determined in any given week, the mean of these clearances was used. Both groups demonstrated a significant increase in mean theophylline clearance over time (from 16.09 and 18.60 ml/h/kg to 28.65 and 24.73 ml/h/kg for the cholestatic and noncholestatic groups, respectively). The mean slope, an indicator of the average rate of change of theophylline clearance, was 1.4 for the noncholestatic group and 2.5 for the cholestatic group, indicating that the theophylline clearance for neonates with cholestasis was not significantly different from that for neonates with normal liver function (p = 0.61) over time.