Background: TRIO-012 is a double-blinded multinational phase III trial that randomized 1,144 patients with advanced breast cancer to receive first-line docetaxel in combination with ramucirumab (anti-VEGFR2) or placebo. We investigated the association of genotype (single nucleotide polymorphisms, SNPs) with the phenotype (hypertension, HT as a treatment-emergent adverse event) to seek genetic predispositions to ramucirumab toxicity. Methods: In this study, 220 SNPs were selected from literature related to anti-angiogenic pathways, drug metabolism/transport, immune regulation, and hypertension. SNPs were genotyped using germline DNA on the platforms, Sequenom iPLEX Gold and Pyrosequencing. Genotype data was filtered for deviations from Hardy Weinberg Equilibrium and minor allele frequency of > 0.05. Study subjects provided ethics-committee approved prospective consent for this genetic study. 257 Caucasian subjects were analysed here from the docetaxel-ramucirumab arm. Toxicity grades 0-1 (n = 208 controls; low toxicity) vs. grade > 2 (n = 49 cases, high toxicity) were tested for genetic associations. Dominant genotypic model was assumed; Chi-square test with 10000 permutations were employed (Golden Helix-SVS v8.3) and p < 0.05 considered statistically significant. Results: VEGF-R2 (rs17709898) conferred protection (OR 0.51 [0.26-0.96]) and rs7691507 conferred risk (OR 2.01 [1.07-3.77]). Polymorphism in ABCB1 (MDR1), rs2235067 conferred risk (OR 2.37[1.21-4.64]). SNPs (rs9508033, rs722503 and rs3794405) in VEGF-R1 and NR1I3 (rs2307418 and rs5085) showed association (risk and protection, respectively). Conclusions: The association of VEGF- R2 rs17709898 with HT is consistent with the known mechanism of ramucirumab VEGF-R2–directed antibody. rs17709898 is in linkage disequilibrium with rs1870377, a variant previously shown to be associated with HT. Similarly, the association of VEGF-R1 with HT suggests compensatory pathways may have a role in anti-angiogenic toxicity. None of the polymorphisms in the VEGF ligand (21tagSNPs) were associated with hypertension. Confirmation of these findings in ongoing ramucirumab studies may permit risk stratification of ramucirumab therapy.