Background: Bevacizumab (Beva) is no longer unanimously recommended in the management of breast cancer (BC). Given the absence of faithful predictors of Beva treatment outcome, we made the hypothesis that constitutional gene polymorphisms could play a role in this context. We report the pharmacogenetic ancillary study of the prospective COMET trial conducted in advanced BC patients (pts) receiving first-line Beva associated with paclitaxel. Methods: Relevant targeted gene polymorphisms were analyzed (blood) in 203 prospective pts (mean age 55.3, median follow-up 24 months). VEGFA at positions -2578C > A (rs699947), -1498T > C (rs833061), -634G > C (rs2010963), and 936C > T (rs3025039) were analyzed by PCR-RFLP. VEGFR1 319A > C (rs9582036), VEGFR2 at positions 604C > T (rs2071559), 1192C > T (rs2305948), 1416T > A (rs1870377), IL8 251T > A (rs4073), CYP2C8 139C > T (rs1572080), 399T > C (rs10509681) and ABCB1 at positions 1199 C > TA (rs2229109), 2677G > TAC (rs2032582) were analyzed by Mass-Array Agena. ABCB1 1236C > T (rs1128503) and 3435T > C (rs1045642) were analyzed by pyrosequencing. All fitted HWE. Results: Median progression-free survival (PFS) was 10.8 months. VEGFR1 319A allele was associated with longer PFS (p = 0.03). The VEGFA-1498T allele was significantly associated with both longer overall survival (OS) (p = 0.005) and PFS (p = 0.065). The VEGFA -2578C allele was associated with greater OS (p = 0.002) and PFS (p = 0.071). These two VEGFA polymorphisms were in linkage disequilibrium (p < 0.0001). Multivariate Cox analysis showed that VEGFA -2578 (p = 0.001) and VEGFR2 1416 (p = 0.025) were significant predictors of OS: the score of favorable alleles (VEGFA -2575C and VEGFR2 1416T) was highly associated with OS (p = 0.0003), with median survival at 24 months being 30% for score 0 (95%CI 15-61), 65% for score 1 (95%CI 55-75) and 90% for score 2 (95%CI 67-90). Conclusions: Application of an easy-to-perform low-cost genotyping test may identify strong predictors of Beva outcome in metastatic BC pts. In the current era of precision medicine, a pharmacogenetic-based personalized Beva therapy deserves to be prospectively validated in BC pts. Clinical trial information: 2012-A00244-39.