To further investigate the early course of cystic fibrosis (CF), specifically to examine factors contributing to energy imbalance, we examined resting energy expenditure (REE) (by indirect calorimetry) per unit body weight and metabolically active body cell mass (by total body potassium), in relation to CF genotype (by genomic DNA analysis), CF pancreatic phenotype, and markers of pulmonary inflammation (from bronchoalveolar lavage fluid). Eighteen subjects with presymptomatic CF who were less than 2 years of age (n = 11, delta F508/ delta F508 genotype; n = 15, pancreatic insufficiency phenotype), identified by newborn screening, were compared with age-, sex-, and length-matched control subjects (n = 13). Those with the delta F508/ delta F508 genotype had significantly higher mean REE expressed per unit body weight (125%) and body cell mass (115%; p < 0.03). Those with other genotypes (n = 7) did not, as a group, have significantly different mean REEs, but individuals with known "severe" genotypes had REEs in the high range and those with a pancreatic-sufficient phenotype had significantly lower REE than those with a pancreatic-insufficient phenotype (p < 0.05), and REEs were in the normal range. Examination of bronchoalveolar lavage fluid revealed positive culture results (7/10) but variable colony counts, neutrophil percentages, and concentrations of interleukin-8 and interleukin-1 beta equally in both CF genotype groups. These markers of pulmonary inflammation were not correlated, individually or collectively, with REE or genotype. We conclude that genotypic variations in energy balance are detectable early in CF unrelated to lung inflammation. Subclinical defects in body composition and pulmonary integrity occur early in CF and, in combination with increased cellular metabolic activity, have important clinical implications with respect to early diagnosis and management.