Abstract Background: Dornase alpha improves sputum clearance and pulmonary function in patients with moderate bronchiectasis and cystic fibrosis (CF). Several studies have demonstrated variable adherence to treatment regimens in patients with CF. We aimed to compare self-reported adherence with computer based dispensing records of dornase alpha. Method: Direct interview of adherence to dornase alpha was compared with pharmacy-dispensing records during a 12-month period. The reasons for dornase alpha usage, and change in lung function in three groups of patients were compared (group 1 ( n=42): positive trial, continuing therapy; group 2 ( n=13): positive trial, ceased therapy; group 3 ( n=22): negative trial). Ninety patients with CF were surveyed. Patients who had ceased dornase alpha provided reasons for drug cessation. Lung function and anthropometric data were collected prior to dornase alpha treatment and at 3 years. Health care professionals rated adherence to therapy. Results: Of the 42 patients on dornase alpha, the average utilisation was 197 days (54%). From dispensing records, 24% of patients were classified as good adherence, 46% as moderate adherence and 30% as poor adherence. Eighty-two percent claimed to use dornase alpha therapy more than 20 days/month, whereas dispensing records showed that only 24% of collected sufficient drug supplies. Health professionals’ assessment of adherence of therapy was often incorrect and an overestimation was more common than underestimation. The change in FEV 1 3 years after trial was not significantly different between groups. There was a negative correlation between initial response to dornase alpha and baseline FEV 1 ( r=−0.44, P=0.001), however, initial response was not related to the change in FEV 1 over 3 years ( r=0.20, P=0.16). Conclusion: There is variability in adherence to dornase alpha in adults with CF and patient self-reporting is likely to over-estimate drug collection from the pharmacy. Further study of the long-term effects of dornase alpha is required. To date, proven interventions to enhance adherence are limited and require investigation in CF.