Angiogenesis plays an important role in growth, progression, and metastasis of tumors. The most important regulator of angiogenesis is vascular endothelial growth factor (VEGF). VEGF expression has been associated with advance stage and poor survival of several cancers. In the present study we evaluated the association of functional polymorphisms in the VEGF gene with colorectal cancer development, prognosis, and survival. Three hundred twelve consecutive patients with surgically treated colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from paraffin-embedded tissue and five VEGF (−2578C>A, −1154G>A, −634G>C, −460T>C, and +936C>T) gene polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism assay. VEGF −2578C>A, −1154G>A, −634G>C, −460T>C, and +936C>T genotype and allele frequencies were similar among patients and controls. There was a trend showing carriers of the −2578A and +936T alleles more frequent among patients with CRC, but these differences did not reach statistical significance. Furthermore, no correlation was found between all these variants and tumor characteristics like size, histological grading, positive regional lymph node metastases or tumor stage. However, the −2578AA, −634CC, and +936TT genotypes found to be related with a significantly lower overall survival in our study. In conclusion, VEGF gene polymorphisms were found to be an independent prognostic marker for Greek CRC patients.