Vascular endothelial growth factor (VEGF) gene polymorphisms have been associated with an increased risk of developing a wide variety of disorders from diabetes to neurodegenerative diseases suggesting functions not confined to its vascular effects originally described. Based on the VEGF protective roles undisclosed in pathological conditions, we evaluate whether VEGF variability might be a determinant also for longevity. Four polymorphisms (-2578C/A, -1190G/A, -1154G/A and -634G/C) within the VEGF gene promoter region in 490 unrelated Italian healthy subjects have been analysed. Significant changes of allele, genotype (-2578/AA versus -2578/CC: OR=2.08, p=0.007; -1190/AA versus -1190/GG: OR=2.01, p=0.011) and haplotype (AAGG: 10.4% versus 14.9%, p=0.03) frequency distributions were observed between young/elderly (25-84 years old) and long-lived (85-99 years old) subjects. These results suggest that VEGF gene variability can be inserted among the genetic factors influencing the lifespan.