Apnea occurs commonly in preterm infants. Theophylline is used as prophylaxis and treatment. Apart from improving ventilatory function, theophylline may also have metabolic effects, including an effect on glucose metabolism and lipolysis. No data are available on the effect of theophylline on glucose production and lipolysis in preterm infants at start of medication. Ten preterm infants with gestational ages of < or = 32 wk, postnatal ages of 16-84 h, and birth weights > 900 g were recruited. Hepatic glucose production and lipolysis were measured by use of gas chromatography/mass spectrometry after constant rate infusion of [6,6-2H2]glucose and [2-13C]glycerol tracers. Plasma glucose levels increased after theophylline administration (mean +/- SD, 4.0 +/- 1.9 mmol/L before and 4.7 +/- 2.1 mmol/L after start of therapy), whereas the rate of glucose production decreased (6.0 +/- 2.5 mg.kg-1.min-1 and 4.3 +/- 1.9 mg.kg-1.min-1, respectively). The plasma glycerol concentration did not show any change after theophylline administration (154 +/- 257 mumol/L before and 217 +/- 258 mumol/L after), and the same was true for the rate of glycerol production (5.9 +/- 2.6 mumol.kg-1.min-1 before and 6.7 +/- 3.0 mumol.kg-1.min-1 after). The fraction of glycerol converted into glucose did not change significantly, although the percentage of glucose derived from glycerol increased after theophylline administration. The results are in line with the lack of adverse metabolic effects at start of theophylline treatment in the preterm infant.