We estimated direct medical costs of care and important determinants of the costs in patients with cystic fibrosis (CF), including therapy with recombinant human DNase (rhDNase). Costs were estimated with resource use data from the Epidemiologic Study of Cystic Fibrosis. Ordinary least squares regression was used to determine the effect of clinical and demographic variables on individual cost of care. The estimated cost of caring for 303 patients in Alberta was $2,279,801 in 1996. The mean cost of care was $7524 (range $386-92,376)/patient. Regression results indicated that age and forced expiratory volume predicted had a negative association with costs. Being female, receiving rhDNase, and having Pseudomonas aeruginosa or Burkholderia cepacia were all associated with high costs. Our estimates indicated large interindividual variation in cost of care for patients with CF.