Background: The VEGF-pathway plays an important role in angiogenesis and is a therapeutic target. Germline genetic variation in this pathway has been associated with disease prognosis but variants with established molecular function are lacking. Thus, we have selected putatively functional variants in the VEGF-pathway genes for testing their association with progression-free survival (PFS) in NSCLC patients. Methods: We selected 11 single-nucleotide polymorphisms (SNPs) in 23 genes of the VEGF-pathway (www.pharmgkb.org) due to their association with gene expression in lymphoblastoid cell lines (Paré-Brunet et al., AACR 2008;#4332), and a further 21 SNPs were identified from the literature and bioinformatics. These 32 SNPs were genotyped in 154 Caucasian stage I-III NSCLC patients by TaqMan. Associations with PFS were tested by Cox regression using an additive model and controlling for disease stage. SNPs were also examined for association with gene expression in tumor samples from a subset of patients and luciferase assays. Results: Five SNPs in KRAS, two in FLT1, one in HIF1A and one in VEGFA associated with PFS (p<0.05, additive model). For three of these variants, the associations were supported by a correlation with gene expression. VEGFA -1154GG genotype patients had greater median PFS (55.3 months) than AG (14.6) and AA patients (11.0; p<0.05), and 39% lower VEGFA tumor expression than AG/AA patients (p<0.05). KRAS 26478TT patients had shorter PFS (5.8) than CT (11.6) and CC patients (25.6; p<0.02), and 175% greater KRAS tumor expression (p<0.01) than CT/TT patients. KRAS 9489GG genotype patients had greater PFS (39.0) than GA (25.7) and AA patients (9.1; p<0.01), and the G allele was associated with a 50% reduction of KRAS promoter expression in luciferase assays (p<0.01). Conclusions: In this exploratory study, we have identified germline variants in the VEGF pathway which associate with PFS in NSCLC. Molecular studies have supported these associations, which seem to be mediated through an effect on gene expression. This study proposes novel prognostic germline markers for testing in future studies.