Antiinflammatory therapy with ibuprofen has been proposed to retard the progression of lund disease in cystic fibrosis (CF). The pharmacokinetics and toxicity of ibuprofen were investigated in a randomized, double-blind, placebo-controlled, 3-month dose-escalation study in 19 children with CF, 6 to 12 years of age. The subjects received orally and twice daily 300 mg of drug during the first month, 400 mg in the second month, and 600 mg in the third month. Ibuprofen pharmacokinetics and evaluation for adverse effects were performed at the beginning and end of each month. The dose of ibuprofen was increased if peak plasma concentration (Cmax) was less than 50 micrograms/ml. To preserve the blind nature of the study, the dose in matched subjects taking placebo was also increased. The subjects randomly assigned to receive ibuprofen (n = 13) completed 26 months of treatment; placebo subjects (n = 5) completed 12 months. With dose escalation, Cmax and the area under the concentration-time curve from zero to infinity significantly increased (p less than 0.01). The pharmacokinetics of ibuprofen in 13 children with CF who received 13.4 +/- 4.1 mg/kg (mean +/- SD) were compared with those in four healthy children who received a similar dose. Peak plasma concentration (48 +/- 17 micrograms/ml) was decreased by 27% (p = 0.06), the area under the concentration-time curve (6.1 +/- 1.7 mg.min/ml) was decreased by 46% (p less than 0.001), apparent total clearance (2.3 +/- 0.6 ml/min.kg-1) was increased by 77% (p less than 0.01), and apparent volume of distribution during terminal phase (291 +/- 91 ml/kg) was increased by 84% (p = 0.01) in the children with CF. Time to Cmax (66 +/- 20 minutes) and elimination half-life (92 +/- 27 minutes) were not significantly different. No subjects were withdrawn from the study because of side effects. No adverse effects could be attributed to ibuprofen. Thus ibuprofen administration has no significant toxic effects, but Cmax will need to be monitored for effective dosing in patients with CF.