Background: Pulmonary decline in CF is heterogeneous, with socio-environmental factors contributing to this variability. Few studies have attempted to disentangle the effects of tobacco smoke exposure and socioeconomic factors on lung function deterioration in pediatric CF. The current study evaluates their contributions longitudinally across the entire U.S. CF care network population. Methods: Data from the CF Foundation Patient Registry were obtained on all individuals who at the end of 2016 were 6–18 years old. Lung function measures (ppFEV1) for each person were calculated at each attained age. Multivariable analyses used mixed modeling to assess the impact of smoke exposure and socioeconomic factors on initial lung function and change over time. Results: The sample included 10,895 individuals contributing 65,581 person years. At age 6, ppFEV1 of smoke-exposed children was 4.7% lower than among unexposed. The deficit persisted through age 18. In adjusted mixed models, smoke exposure and socioeconomic factors had independent, additive associations with lung function. Median ppFEV1 declined 2.4% with smoke exposure, 4.9% with lower paternal education, 0.3% with public insurance, and increased 0.2% with each $10,000 annual household income. The effect of smoke exposure on ppFEV1 was larger in disadvantaged children compared to privileged counterparts (3.2% vs 1.2%). Conclusions: Smoke exposure and socioeconomic factors are independent risk factors for decreased ppFEV1 in pediatric CF. Smoking cessation strategies should be emphasized at the time of CF diagnosis and reiterated during infancy and early childhood. Interventions may be prioritized in disadvantaged families, where the exposure has a disproportionately large effect.