BACKGROUND: Chronic endobronchial sepsis and profuse airway secretions dominate pulmonary disease in cystic fibrosis. Recombinant human DNase I (dornase alfa) reduces the viscoelasticity of airway secretions and hence may improve clearance of airway secretions. OBJECTIVES: To evaluate the long-term influence of dornase alfa on disease progression by performing a case-controlled study with dornase alfa over a period of 4 years. METHODS: A cohort of patients with cystic fibrosis who have been treated with dornase alfa were matched with a control group of patients with cystic fibrosis who had not received treatment with dornase alfa. The patients were matched by pulmonary function, age, and then sex. All available measurements of forced expiratory volume in one second (FEV1), height, weight and sputum bacteriology were collected for periods when the patients were free from respiratory exacerbations. RESULTS: Thirty-eight patients were matched. Slopes of median changes in FEV1 were -2.19 (-3.32, -1.06) in the control group and -0.75 (-1.87, 0.36) in the dornase alfa-treated group (p = 0.076). There were more infective exacerbations per patient year in the control group [3.13 (1.25-4.25)] in comparison to the dornase alfa group [1.25 (0.63-3.0), p = 0.035] over the 4-year treatment period. Antibiotic requirements were also greater with a median 43.75 (17.5-60.0) days of intravenous antibiotic use per patient year in the control group and 16.25 (8.5-44.0) days in the dornase alfa group (p = 0.034). CONCLUSIONS: The trends suggest that dornase alfa may have some influence on disease progression but in view of the limitations of the current study the need for further long-term studies in larger cohorts of patients is emphasised.