Background Disturbed vascular endothelial growth factor (VEGF) production during early heart morphogenesis causes endocardial cushion malformation, which results in congenital heart disease (CHD). We tested whether functional VEGF −460T/C and +405G/C polymorphisms that have an impact on VEGF levels were associated with CHD. Methods Dried blood samples were collected from 102 CHD children and 112 healthy control neonates. Genotyping was done with polymerase chain reaction–restriction fragment length polymorphism (VEGF +405G/C) and real-time polymerase chain reaction methods (VEGF −460T/C). Results VEGF −460C allele frequency was similar in control and CHD subjects. VEGF +405C allele was less prevalent in controls than in CHD subjects (0.21 vs 0.42, P < .001). Having VEGF +405C presented increased risk for CHD (odds ratio [OR] 1.72, 95% CI 1.32-2.26). VEGF −460CT/+405CC allele associations did not occur in controls but in CHD patients (0% vs 13%, OR 2.26, 95% CI 1.93-2.64), whereas −460CT/+405GG allele association was more prevalent in controls (32% vs 16%, OR 0.58, 95% CI 0.37-0.89). Conclusions VEGF gene and allele associations may be associated with increased risk of CHD.