RATIONALE Inhaled tobramycin has been shown to transiently clear Pseudomonas from lower airways in early cystic fibrosis (CF), but does not markedly reduce lung inflammation, a key factor in disease progression. OBJECTIVE Test the hypothesis that systemic antibiotics are more effective than inhaled antibiotics for reducing lower airways inflammation. METHODS Clinically stable CF children with recent Pseudomonas were randomized to receive 4 weeks of inhaled tobramycin or 2 weeks of systemic antibiotics (intravenous ceftazidime and tobramycin). Bronchoalveolar lavage fluid was obtained just before and 4-6 weeks after treatment. The primary outcome was change in % neutrophils in lavage fluid. RESULTS Fifteen subjects (inhaled = 6, systemic = 9) completed the protocol. Three Systemic Group subjects could not have central venous access established and were treated with oral ciprofloxacin (plus inhaled tobramycin) for 2 weeks as an alternative "systemic" regimen, per protocol. Groups were well matched in age, markers of disease severity, and initial % neutrophils. The Systemic Group showed a modest median change in percent neutrophils (-7%) which was not statistically significant compared to inhaled (+5.4%, P = 0.07). However, the Systemic Group had significantly greater reductions in total cells (-50% vs. -3%, P < 0.01) and neutrophils (-74% vs. -10%, P = 0.02) per ml lavage fluid. Both groups had reduced bacterial quantity after treatment, but there was no significant difference between groups. CONCLUSIONS In clinically stable children with CF, systemic antibiotics result in greater short-term reduction in lower airways inflammation than inhaled antibiotics.