Rationale: Given the role of vascular endothelial growth factor (VEGF) in lung development, we hypothesized that polymorphisms in VEGF-A may be associated with lung function. Objectives: The current study was designed to assess the role of genetic variants in VEGF-A as determinants of airway function from infancy through early adulthood. Methods: Association between five single-nucleotide polymorphisms (SNPs) in VEGF-A and lung function were assessed longitudinally in two unselected birth cohorts and cross-sectionally among infants. Replication with two SNPs was conducted in adults and children with asthma. We investigated the functionality of the SNP most consistently associated with lung function (rs3025028) using Western blotting to measure the ratio of plasma VEGF-A 165b/panVEGF-A 165among homozygotes. Measurements and Main Results: In two populations in infancy, C-allele homozygotes of rs3025028 had significantly higher VmaxFRC, forced expiratory flow 50, and forced expiratory flow 25-75 compared with other genotype groups. Among preschool children (age 3 yr), C allele of rs3025028 was associated with significantly higher specific airway conductance, with similar findings observed for lung function in school-age children. For FEV 1/FVC ratio similar findings were observed among adolescents and young adults (birth cohort), and then replicated in adults and school children with asthma (cross-sectional studies). For rs3025038, plasma VEGF-A 165b/panVEGF-A 165 was significantly higher among CC versus GG homozygotes (P ≤ 0.02) at birth, in school-age children, and in adults. Conclusions: We report significant associations between VEGF-A SNP rs3025028 and parameters of airway function measured throughout childhood, with the effect persisting into adulthood. We propose that the mechanism may be mediated through the ratios of active and inhibitory isoforms of VEGF-A 165, which may be determined by alternative splicing. Copyright © 2012 by the American Thoracic Society.