OBJECTIVES: Pulmonary exacerbations (PEx) lead to substantial morbidity in cystic fibrosis (CF), and guidelines recommend chronic medication including dornase alfa and inhaled tobramycin.  However PEx risk and medication use vary across patients. We aimed to develop a PEx risk score among CF patients not receiving guideline-recommended chronic respiratory medications. METHODS: Patients without evidence of dornase alfa or inhaled tobramycin use in an index year, despite meeting guideline recommended criteria, were identified from the CF Foundation Patient Registry (2002 to 2008).  This sample was randomly split into 2/3 for a development sample and 1/3 for a validation sample.  A multivariable risk score was developed to predict PEx requiring hospitalization or home IV treatment using available patient characteristics. Its predictive performance was assessed in the validation sample. RESULTS: Among 3,069 patient-years, 1,275 (42%) had PEx in the subsequent year. The risk score included, in order of decreasing impact on PEx risk, prior PEx, Pseudomonas aeruginosa, allergic bronchopulmonary aspergillosis, depression, methicillin-resistant Staphylococcus aureus, cystic fibrosis-related diabetes, Burkholderia cepacia, prior use of dornase alfa, bronchodilator use, prior use of inhaled tobramycin and lower FEV1 %-predicted.  Stratifying patients by risk score in the validation sample identified actual risks ranging from 14% in the lowest decile to 90% in the highest. The c-statistic was 0.8. CONCLUSIONS: A PEx risk score for CF patients not receiving guideline-recommended chronic therapies was developed and validated, and identified patients with a wide range of risk. This score could identify high-risk patients in whom chronic therapies should be initiated or continued.