BACKGROUND: Despite improving survival in cystic fibrosis (CF) patients, there is a mortality peak in early adulthood. Defining risk factors that predict significant worsening of lung disease in young adulthood may identify opportunities to improve outcomes in adults. METHODS: We identified 4,680 patients in the Epidemiologic Study of Cystic Fibrosis 1994-2005 with data in both adolescence (age 14.0-17.4 years) and young adulthood (age 18.5-22.0 years) and analyzed 2,267 who had >/=5 encounters and >/=5 measurements of forced expiratory volume in 1 second (FEV(1) ) spanning >/=1 year during both adolescence and young adulthood, and >/=1 encounter with weight and height and >/=1 FEV(1) measurement age 17.5-18.5 years. We compared the annualized rates of decline in FEV(1) during adolescence and young adulthood stratified by best FEV(1) around age 18. Logistic regression was used to identify risk factors associated with substantial decline (>20 points) in FEV(1) % predicted in young adulthood. RESULTS: Annual rate of decline was greater in young adulthood than in adolescence. Risk factors for substantial decline included slower rate of FEV(1) decline, greater FEV(1) variability, faster body mass index (BMI) decline, male sex, chronic inhaled antibiotics, Haemophilus influenzae detection, and absence of multidrug-resistant Pseudomonas aeruginosa in adolescence, and lower than expected FEV(1) and BMI around age 18. CONCLUSIONS: Decline in lung function accelerates in young adults with CF, especially in those with early stage lung disease. Adolescents at risk for substantial decline in lung function in young adulthood have higher FEV(1) and worse nutritional status, among other identifiable risk factors. Pediatr Pulmonol. 2012; 47:135-143. (c) 2011 Wiley Periodicals, Inc.