By improving pulmonary function in patients with cystic fibrosis (CF), recombinant human deoxyribonuclease (rhDNase) may affect resting energy expenditure (REE). To examine this hypothesis, we measured REE by indirect calorimetry in seven patients with CF before (day 0) and 2 weeks after (day 15) administration of aerosolized rhDNase. Baseline REE was higher in all patients than predicted for age, sex, and weight (mean +/- SEM 128 +/- 4.9%; range, 116-147%). After 2 weeks of aerosolized rhDNase, mean forced vital capacity (FVC) (in % of predicted values) improved significantly from 54.1 +/- 2.2 to 66.3 +/- 4.2% (mean improvement, 12.3%; 95% CI, 2.8, 21; P < 0.05) and REE decreased by 11.0% (95% CI 3.2, 17.5; P < 0.05). In addition, the larger the improvement in FVC in response to rhDNase the greater the decrease in energy expenditure (r - 0.88). The REE decreased in all patients who had an increase in FVC and remained unchanged in two patients who had no change in FVC. We conclude that patients with CF whose lung function improve in response to aerosolized rhDNase have an acute and proportionate reduction in their resting energy expenditure.