We hypothesized that elevated hepatic glucose output (HGO) may occur in children with cystic fibrosis (CF) as an early sign of declining insulin secretion and that tolbutamide therapy would correct the defect. We studied eight glucose-tolerant CF patients (mean +/- SD, 9.1 +/- 1.9 y) and five healthy controls (9.0 +/- 1.6 y). Fasting glucose, insulin, and insulin-connecting peptide concentrations were not different in the CF and control subjects; however, meal stimulation tests in the CF patients suggested that insulin secretion was defective in the fed state. HGO (mg.kg-1 body weight.min-1) was 26% higher in the CF patients (4.2 +/- 0.7 versus 3.1 +/- 0.6 in HC) (p = 0.016). When normalized for fat-free mass (mg.kg fat-free mass-1.min-1), HGO was 27% higher in CF (4.9 +/- 0.8 versus 3.8 +/- 0.5) (p = 0.015). However, when expressed as a function of resting energy expenditure (mg.kcal-1), HGO was not significantly different in CF (121 +/- 22) versus healthy controls (116 +/- 30). In seven of the CF group, HGO was re-assessed after a 2-h glucose infusion at a rate of 0.90 +/- 0.02 mg.kg-1.min-1. HGO was suppressed (p < 0.05) by an amount equal to 103 +/- 18% of the glucose infusion rate. Finally, in five CF patients, HGO was re-measured after 2 wk of oral therapy with tolbutamide (750 mg/d). Tolbutamide did not affect HGO (fasting or during the glucose infusion). In conclusion, fasting HGO was elevated in the CF patients in proportion to energy expenditure.