AIM: Besides correlating with prognosis, tumor-driven angiogenesis also seemed able to influence response/resistance to chemotherapy in preclinical models. We examined the role of tumor angiogenesis genotyping in determining clinical outcome in metastatic gastric cancer patients receiving first-line chemotherapy. PATIENTS & METHODS: VEGF-A, VEGF-C, FLT1, KDR and FLT4 genotyping was analyzed in gastric tumors from patients receiving platinum-based first-line chemotherapy. RESULTS: VEGF-A rs25648 correlated with response rate (partial response: 18% among patients showing the VEGF-A rs25648 CT or TT genotype vs 44% among patients showing the VEGF-A rs25648 C genotype; p = 0.04). At multivariate analysis only VEGF-A rs25648 maintained an independent role in determining median progression-free survival (hazard ratio: 1.65 95% CI: 1.12-2.78) and overall survival (hazard ratio: 1.58, 95% CI: 1.17-2.65). CONCLUSION: VEGF-A rs25648 genotyping may help identify a patient subgroup unlikely to benefit from a first-line, platinum-based combination and potential candidates for alternative therapy choices.