In its role as an endothelial cell proliferation and migration factor, vascular endothelial growth factor (VEGF) can affect peripheral circulation, and therefore impact maximal oxygen consumption (Vo_2max). Because of the role of VEGF, and because variation in the VEGF gene has the ability to alter VEGF gene expression and VEGF protein level, we hypothesized that VEGF gene polymorphisms are related to VEGF gene expression in human myoblasts and Vo_2max before and after aerobic exercise training. We analyzed the effects of the VEGF -2578/-1154/-634 promoter region haplotype on VEGF gene expression using a luciferase reporter assay in cultured human myoblasts and found that the AAG and CGC haplotypes resulted in significantly higher hypoxia-stimulated VEGF gene expression than the AGG and CGG haplotypes. Consistent with these results, we found that individuals with at least one copy of the AAG or CGC haplotype had higher Vo_2max before and after aerobic exercise training than did subjects with only the AGG and/or CGG haplotype. In conclusion, we found that VEGF -2578/-1154/-634 haplotype impacts VEGF gene expression in human myoblasts and is associated with Vo_2max. These results have potential implications for aerobic exercise training and may prove relevant in the study of pathological conditions that can be affected by angiogenesis, such as coronary artery disease and peripheral artery disease.