Seventeen patients with cystic fibrosis (CF) and pulmonary exacerbations were randomly assigned to two treatment groups: piperacillin 600 mg/kg/day (P), and piperacillin 600 mg/kg/day plus tobrarmycin (PT), in order to determine the safety and pharmacokinetics of high-dose piperacillin and whether piperacillin alone was effective for the treatment of Pseudomonas infections. The mean half-life of piperacillin was 0.54 hours, with a peak concentration of 232 μg/ml. No differences between P and PT groups were noted in clinical assessment, as judged by Shwachman scores, pulmonary function testing, or weight gain. However, during the course of treatment, quantitative sputum cultures decreased by greater than 102 colony-forming units in only 5 out of 19 Pseudomonas isolates from the P group, compared with 12 of 19 isolates from the PT group (P < 0.03, Chi-square). Although emergence of resistance was not seen, one isolate had an increase in minimum inhibitory concentration from 8 to 128 μg/ml. There were no serious adverse reactions to piperacillin; only one patient developed fever possibly related to piperacillin. Therapy with high-dose piperacillin was safe in children with CF. Treatment with piperacillin alone was less effective than combination therapy with gentamicin for reduction in titer of Pseudomonas in sputum. However, the role of antimicrobial agents in the treatment of CF remains undefined. A double-blind placebocontrolled trial is indicated.