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. © 2010 Wiley-Liss, Inc.