The aim of this study was to determine: (1) the frequency of VEGFA gene locus (6p12) amplification in colorectal cancers, (2) the effect of gene amplification on clinical outcome using two independent colorectal cancer patient cohorts and (3) the relationship between amplification and KRAS or BRAF gene mutation as well as with other RAS/MAPK signalling proteins. Single-punch (n=1280; cohort 1) and multiple-punch (n=195; cohort 2) tissue microarrays were used for dual-labelling fluorescence in situ hybridization (FISH). Amplification was defined as a ratio >2 times for 6p12/centromere 6 signals. Mutation analysis of KRAS (codons 12 and 13) and BRAF (codon V600E) and immunohistochemistry for p-MAPK3/MAPK1, PEBP1, HMMR, p-AKT, PLAU, PLAUR, TP53 and VEGFA were performed on cohort 1. In cohort 1, VEGFA amplification was found in 39/1280 (3%) cases and linked to higher pT stage (P=0.022), higher tumor grade (P=0.024) and vascular invasion (P=0.003). The 5-year disease-specific survival rates were 31% (95% CI 17-46) and 57% (95% CI 54-60) for amplified and nonamplified cases, respectively (P<0.001). Results were confirmed in cohort 2. In multivariable analysis, the relative risk for amplification was 2.09 (95% CI 1.4-3.1; P<0.001) and linked to more frequent BRAF mutation (P=0.015), overexpression of p-MAPK3/MAPK1 (P=0.012) and PLAU (P=0.048) and loss of metastasis suppressor protein PEBP1 (P=0.047). VEGFA gene locus amplification highlights a small but remarkably aggressive subgroup of colorectal cancers. Further studies are needed to elucidate the potential role of amplification as a prognostic or predictive biomarker in both metastatic and nonmetastatic patients.