Background: The EPIC Observational Study is an ongoing prospective cohort study investigating risk factors for and clinical outcomes associated with early Pseudomonas aeruginosa (Pa) acquisition in young children with cystic fibrosis (CF). Objectives and Hypothesis: To describe the baseline characteristics of the cohort and evaluate associations between potential risk factors and nutritional and respiratory characteristics at enrollment. We hypothesized that distinct demographic and environmental risk factors could be identified for poorer nutritional status and lung function at enrollment. Methods: During 2004-2006, 1,700 children with CF were enrolled at 59 US CF centers. Children ≤12 years were eligible if they had no prior Pa infection (Pa-Never) or, if prior isolation of Pa from respiratory cultures, at least a 2-year history of Pa negative cultures (Pa-Past). Results: One thousand one hundred seventeen participants (65.7%) were Pa-Never and 583 (34.3%) Pa-Past. Pa-never patients had a lower proportion of CFTR genotypes with both mutations in functional classes I, II, or III), higher lung function and less respiratory symptoms. Diagnosis after newborn or prenatal screening was associated with significantly higher mean weight, height, and FEV1 at enrollment, while maternal smoking during pregnancy appeared to worsen these parameters. Conclusions: Children in this cohort with a remote history of Pa infection had a higher proportion of CFTR genotypes associated with severely reduced CFTR function as well as lower lung function and more respiratory symptoms than those without prior Pa infection. These observed differences in respiratory indices may reflect the impact of prior Pa airway infection and/or of CFTR genotype or other genetic factors predisposing both to earlier Pa acquisition and more severe lung disease. Key characteristics associated with nutritional and pulmonary status at enrollment included diagnosis after prenatal or neonatal screening (protective) and in utero cigarette exposure (harmful). © 2010 Wiley-Liss, Inc.