OBJECTIVES: To characterize the onset of persistent signs and symptoms of cystic fibrosis (CF) lung disease and identify characteristics that predict onset. STUDY DESIGN: Patients in the Epidemiologic Study of CF who were <4 years of age at enrollment and had >/=2 years of follow-up were included. We defined persistence as a sign or symptom that was present during two consecutive encounters separated by 60-365 days, and persistent clubbing as >/=50% of encounters with clubbing within 365 days. Predictors were assessed in a Cox proportional hazards model for age at first occurrence of each symptom. RESULTS: Each sign or symptom met the criterion of persistence in a substantial proportion of patients during a follow-up period of 7 +/- 3 years (mean +/- SD; range 2-12). Risk factors that predicted earlier onset of signs and symptoms included pancreatic enzyme use, Pseudomonas aeruginosa infection, and prior diagnosis of asthma. Other risk factors had variable effects on signs and symptoms. CONCLUSIONS: Signs and symptoms of lung disease begin early in CF. Risk factors previously reported for lower forced expiratory volume in 1 sec are also associated with earlier onset of persistent signs and symptoms of CF lung disease, but their impact varies. Pediatr Pulmonol. 2012. 47:966-972. (c) 2012 Wiley Periodicals, Inc.