BACKGROUND: Understanding early-life risk factors for childhood death in cystic fibrosis (CF) is important for clinical care, including the identification of effective interventions. METHODS: Data from the Epidemiologic Study of Cystic Fibrosis (ESCF) collected 1994-2005 were linked with the Cystic Fibrosis Foundation Patient Registry (CFFPR) demographic and mortality data from 2013. Inclusion criteria were >/=1 visit annually at age 3-5 years and >/=1 FEV1 measurement at age 6-8 years. Demographic data, nutritional parameters, pulmonary signs and symptoms, microbiology, and FEV1 were evaluated as risk factors for death before age 18 years. Multivariable Cox proportional hazards regression was used to model the simultaneous effects of risk factors associated with death before age 18 years. RESULTS: Among 5365 patients enrolled in ESCF who met inclusion criteria, 3880 (72%) were linked to the CFFPR. Among these, 191 (5.7%) died before age 18 years; median age at death was 13.4 +/- 3.1 years. Multivariable regression showed clubbing, crackles, female sex, unknown CFTR genotype, minority race or ethnicity, Medicaid insurance (a proxy of low socioeconomic status), Pseudomonas aeruginosa on 2 or more cultures, and weight-for-age <50th percentile were significant risk factors for death regardless of inclusion of FEV1 at age 6-8 years in the model. CONCLUSION: We identified multiple risk factors for childhood death of patients with CF, all of which remained important after incorporating FEV1 at age 6-8 years. Among the factors identified were the presence of clubbing or crackles at age 3-5 years, signs which are not routinely collected in registries.