BACKGROUND AND AIM The gastroduodenal ulcer (GDU) mostly develops on the lesser curvature side of stomach and the anterior wall of duodenal bulb, irrespective of the etiologies including Helicobacter pylori infection, non-steroidal anti-inflammatory drugs, alcohol, etc. However, a clear explanation as to why ulcers are prevalent in these areas has still not been given. The current study was designed to evaluate whether the vascular endothelial growth factor (VEGF) polymorphism could predict susceptibility to GDU through deranged angiogenic activities. METHODS A large scale case-control study based on known single nucleotide polymorphisms (SNP) of VEGF and another case control study based on the novel SNP of VEGF was performed through the SNP-IT assay using the SNP stream 25 k system. A site-directed mutagenesis and functional assay was executed to document the biological effect of a novel VEGF SNP on angiogenesis. RESULTS Even though the case-control study between non-ulcer dyspepsia (NUD) and gastric ulcer (GU) patients was done in 10 SNP of the VEGF gene including -2488C/T, -634G/C, -7C/T, 3436G/C, 6112C/A, 6894C/T, 9374G/A, 9812C/T, 13128C/T, and 13553C/T, the analysis showed no statistically significant association between NUD and GU. Denaturing high-performance liquid chromatography analysis could identify two novel SNP of the VEGF gene, -1780T/C and IVS-99 G/C, among which -1780T/C showed a very strong association between NUD and GDU, presenting with OR=2.93 on codominant analysis (P<0.001), OR=8.62 on dominant analysis (P<0.001), and OR=3.21 on recessive analysis (P<0.001). The promoter assay using a site-directed mutagenesis and in vitro angiogenesis assay showed repressed transcription of the VEGF gene in gastric epithelial cells and defective tube formation in endothelial cells, both transfected with a plasmid containing -1780C/C mutant of VEGF gene. CONCLUSION The novel VEGF polymorphism -1780T/C could significantly predict the predisposition to GDU after the exposure to etiologic risks, based on defective angiogenic activity.