Chronic therapy with the macrolide antibiotic azithromycin (AZM) is widely practiced in the treatment of patients with cystic fibrosis (CF) and chronic lung infection with Pseudomonas aeruginosa. Azithromycin dosage is variable, based on published studies, and not supported by pharmacokinetic data. This study describes the pharmacokinetics of the long-term administration of AZM (500 mg per day) in CF patients. AZM concentrations were quantified in the plasma, blood, isolated polymorphonuclear neutrophils (PMNNs), and sputum of 8 adult CF patients. The AZM distribution t1/2 was 0.1 hours in plasma. The (mean±standard deviation) elimination t1/2 was 102±20 hours in plasma, 180±68 hours in blood, and 289±166 hours in PMNNs. The Cmax of AZM was 0.67±0.31 mg/L in plasma and 2.01±0.74 mg/L in blood, of which 1.44±0.69 mg/L was found in PMNNs. In sputum the concentration of AZM ranged from 12 to 53 mg/L and was still detectable at concentrations in the range 4 to 27 mg/L 10 days after the last dose. On average, the concentration in PMNNs was 2100 times the Cplasma 24 hours after dosing AZM. These results confirm the accumulation of AZM in PMNNs. The authors conclude that sputum levels are elevated far above plasma and blood concentrations. The long t1/2 in blood and PMNNs and the slow decrease in sputum levels indicate a less frequent dosing schedule (for instance once weekly) should be studied in future clinical trials of AZM in patients with cystic fibrosis.