BACKGROUND: Cystic fibrosis (CF) is the most common life-shortening genetic disorder among white individuals worldwide. Previous estimates of the costs of medical care have been based on expert opinion rather than observed costs. Accurate cost estimates are needed to enable evaluation of the cost-effectiveness of new interventions and prenatal genetic screening recommendations. OBJECTIVE: To evaluate the cost of medical care for patients (N = 136) served by a health maintenance organization with a CF center. METHODS: Retrospective analysis of data from computerized cost databases and the Cystic Fibrosis Foundation annual survey. Severity of disease was classified based on the percent predicted forced expiratory volume at 1 second. RESULTS: The annual cost of medical care in 1996 averaged $13 300 and ranged from $6200 among patients with mild disease to $43 300 among patients with severe disease. Of total costs, 47% were from hospitalization, 18% were from DNase (Pulmozyme), 12% were from clinic visits, and 10% were from outpatient antibiotics. When the observed costs were used to estimate the costs of medical care for the entire population of CF patients in the United States, these costs were estimated to be $314 million per year in 1996 dollars. CONCLUSIONS: We conclude that the cost of medical care for CF varies greatly with severity but is substantial even among patients with mild disease. These findings underscore the need for strategies to ensure good health insurance coverage and high quality care for all individuals with this condition.