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Background: The vascular endothelial growth factor-A (VEGF-A) and Cyclooxygenase-2 (Cox-2) polymorphisms have been implicated in colorectal cancer (CRC). VEGF-A and Cox-2 polymorphisms might modify the levels of protein expression and may have a considerable influence on disease phenotype, which may have important clinical/genomic implications. Aims: To evaluate single nucleotide polymorphisms (SNPs) in the VEGF-A, and Cox-2 genes and their prognostic values for patients operated on for CRC; and to investigate possible interactions between these genetic variations and clinicopathologic characteristics in CRC. Methods: VEGF-A and Cox-2 SNPs have been analyzed in 230 prospective patients who underwent surgical resection, and had a minimum of 5 years follow-up. DNA was isolated from leukocyte using extraction and purification kit, followed by amplification by polymerase chain reaction (PCR). Real-time analysis was used for genotyping VEGF-A and Cox-2 SNPs through the TaqMan ® SNP Genotyping Assay. Results: We determined frequencies of four VEGF-A biallelic SNPs with twelve haplotypes: (-2578C>A: CC = 36.1%; CA = 46.1%; AA = 17.8%; -460T>C: TT = 34.3%; TC = 45.7%; CC = 20%; -634G>C: GG = 48.7%; GC = 40.4%; CC = 10.9%; +936 C>T: CC = 74.3%; CT = 23.5%; TT = 2.2%), and three COX-2 SNPs with nine haplotypes (-1195A>G: AA = 63.5%; AG = 31.3%; GG = 5.2%; 8437T>C: TT = 44.3%; TC = 43.9%; CC = 11.7%, -765G>C: GG = 58.3%; GC = 31.7%; CC = 1.3%). A high frequency of the wild genotype Cox-2 -765GG and polymorphic genotype Cox-2 -1195GG and VEGF-A -634CC was found in an Asiatic (mostly Japanese) population. VEGF-A -2578C>A, and -460T>C were associated to familial history of cancer. There were associations between wild homozygous VEGF-A (-2578CC; -460TT; -634GG; +936CC), and wild homozygous Cox-2 (-1195AA; 8437TT; 765GG) SNPs with pre-operative CEA, histological type, peritumoral deposits, perineural and angiolymphatics invasion, lymph node metastases or pN, and stage IV disease, p < 0.04. Wild homozygous genotype of VEGF-A and Cox-2 were significantly correlated with a worst progression-free survival and overall survival when compared to the combined heterozygous or recessive genotypes in a multivariate analysis. Conclusions: 1. Wild homozygous VEGF-A and Cox-2 SNPs were associated to disease progression and survival in patients with advanced colorectal cancer; 2. VEGF-A and Cox-2 SNPs may be useful markers of aggressiveness in these patients; 3. Molecular data may orientate the appropriate target therapy in novel clinical trials.