Theophylline is administered to preterm infants with pulmonary disease to improve pulmonary function and reduce apneic episodes. Because it potentially mediates both a-and β-receptor-effector mechanisms, we tested the hypothesis that it increases lipolysis, gluconeo-genesis from glycerol, and energy expenditure in 16 preterm infants, eight of whom were treated therapeutically with theophylline for apnea of prematurity (T) and eight of whom were controls (C). Mean ± SD postnatal ages were 4.8 ± 1.9 wk (T) and 2.4 ± 0.9 wk (C) (p < 0.01). Corrected gestational ages were 35 ± 1.6 wk (T) and 34 ± 0.5 wk (C) (p = NS). Body weights were 1.69 ± 0.13 kg (T) and 1.70 ± 0.23 kg (C) (p = NS). All infants were clinically stable, breathing room air, fed enterally, and receiving no diuretics, steroids, or antibiotics. Lipolysis, hepatic glucose production, and gluconeogenesis from glycerol were measured using [2-13C]glycerol and [6,6-3H2] glucose tracers. Body water and energy expenditure were measured by the2H218O method. Body water volumes were 68.5 ± 3.4% body weight (T) and 70.2 ± 3.4% (C) (p = NS), suggesting fat was 10-13% of body weight in both groups. Mean daily energy expenditure was 65 ± 22 kcal/ kg body weight/d (T) versus 59 ± 5 kcal/kg body weight/d (C) (j) = NS). Between 4 and 6 h after a feeding, glucose production rates were 40.5 ±4.3 μmol/kg/min (T) and 37.6 ± 4.8 jumol/kg/min (C) (p = NS). Plasma glycerol appearance rate, an index of lipolysis, was nearly equivalent in both groups, averaging 9.6 ± 2 μmol/kg/min (T) and 9.3 ± 2.4 μmol/kg/min (C). Glycerol accounted for 10 ± 2% (T) and 10 ± 4% (C) of new glucose carbon (p = NS). We conclude that energy expenditure, body composition, lipolysis, glucose production, and gluconeogenesis from glycerol are not altered in preterm infants with apnea of prematurity treated therapeutically with theophylline, and therefore speculate that theophylline treatment is not a major deterrent of weight gain in premature infants with lung disease. The data suggest further that lipid mobilization may already be stimulated maximally 4 to 6 h after the last feeding in preterm infants studied 1 mo after birth.