BACKGROUND Vascular endothelial growth factor (VEGF) is important in atherosclerotic development. We examined two VEGF polymorphisms, including +405 C/G (rs2010963) and -2578C/A (rs699947), to assess their relation to the extent of coronary atherosclerosis. METHODS We recruited 398 patients with advanced coronary artery disease (CAD). Angiographic "clinical vessel score" (CVS, 1-3 vessels) and "diffuse score" (DS, 0-11.5) were used to evaluate the extent of coronary atherosclerosis. CVS are further categorized into single- (SVD) and multi-vessel disease (MVD: 2 and 3 vessels). Genotyping was performed by TaqMan assay. RESULTS The frequency of +405 C/G genotype was correlated with CVS and DS (P = 0.016 and 0.016, respectively). The +405C allele frequency was significantly increased in patients with MVD (P = 0.020). The odds ratio (OR) for the CC to the GG genotype was 2.92 (95% confidence interval (CI): 1.31-6.55, P = 0.007). Univariate and logistic regression analysis showed a significant independent association of +405 C/G genotype with SVD/MVD (P = 0.010 and 0.015, respectively) in the recessive model. Furthermore, there is a synergistic effect of CC genotype and diabetes on the occurrence of MVD (P = 0.001 for interaction). There is also a significant independent association of +405 C/G genotype in the recessive model with DS in the uni- and multivariate regression analysis (P = 0.013 and 0.005, respectively). No association was found between VEGF -2578C/A polymorphism and both atherosclerotic parameters. CONCLUSIONS The VEGF +405C/G polymorphism is a novel genetic factor to influence the extent of coronary atherosclerosis in the Chinese CAD population.