Despite aggressive nutritional therapy, low body weight and protein catabolism are common problems in children with cystic fibrosis. Previous studies by our group and others have demonstrated improvement in both height and weight in children with cystic fibrosis who were treated with human recombinant GH, and our group has recently documented improved clinical status and lean tissue mass as well. The purpose of this report is to summarize our findings of the effect of GH on whole body protein kinetics in cystic fibrosis and to relate these findings to changes in TNF-alpha levels. We conducted a 1-yr study of 19 prepubertal children with cystic fibrosis (age 7-12 yr, all <94% of ideal body weight). Ten children were randomly assigned to take daily injections of GH (0.3 mg/kg.wk), and nine were randomly assigned to be controls. Baseline results from the subjects with cystic fibrosis were compared with results obtained from nine age- and gender-matched healthy children. Whole body protein turnover was measured at baseline and every 6 months using the stable isotope [1-(13)C]leucine and mass spectrometric analysis. Leucine rate of appearance, a measure of protein catabolism, was similar in both cystic fibrosis subgroups at baseline and was significantly higher than in the control children without cystic fibrosis. Treatment with GH resulted in a significantly lower leucine rate of appearance, as well as significantly lower leucine oxidation. The rate of protein synthesis, as calculated from these numbers, actually decreased in the cystic fibrosis subgroup. TNF-alpha levels were higher in both cystic fibrosis subgroups than in controls and correlated with leucine rate of appearance. The results of this study suggest that one reason GH improves body weight and lean tissue mass is due to improved whole body protein catabolism and improved efficiency of whole body protein kinetics.