OBJECTIVE: To assess the relationship between level of use of recombinant deoxyribonuclease I (rhDNase) therapy and costs of respiratory-related care in patients with cystic fibrosis. DESIGN: Retrospective, cohort study using healthcare claims data from a large New England health insurer. PATIENTS: All cystic fibrosis patients five years of age and older who began therapy with rhDNase in 1994 (the year it was first marketed in the US). Healthcare claims were compiled for six months prior to first receipt of rhDNase (pretreatment) and for 30 months subsequently (follow-up). Patients were stratified according to their level of rhDNase use during follow-up, based on whether it was above or below the median number of therapy days for the sample. MAIN OUTCOME MEASURES: Costs of rhDNase, all antibiotics, and all respiratory-related outpatient (physician, home health, hospital outpatient) and inpatient care were included. All costs were expressed on an annualized basis. RESULTS: Twenty-four patients with cystic fibrosis who began treatment with rhDNase in 1994 met all entry criteria; the median number of therapy days over a 30-month period was 355. Among patients with low (i.e., below the median) rhDNase use (n = 12), mean ± SD annualized costs of respiratory-related care increased by almost $17000 between pretreatment and follow-up, from $29251 ± $37919 to $46109 ± $40944. Among high-use patients (n = 12), costs decreased by approximately $2500, from $37178 ± $48476 to $34592 ± $22591. The change in both groups was accounted for primarily by a change in the number of respiratory-related hospitalizations. CONCLUSIONS: Prolonged use of rhDNase may reduce costs of respiratory-related care in patients with cystic fibrosis; further study is required, however, to confirm these findings.