Background: TRIO-012 is a double blinded, multinational trial that randomized 1,144 patients with advanced breast cancer to receive first-line docetaxel (Doc) in combination with ramucirumab or placebo. Our objective is to address genetic predisposition to Doc toxicity. In this independent validation study, we selected single nucleotide polymorphisms (SNPs) previously associated with taxane-induced adverse events (AEs; fatigue, myalgia, peripheral neuropathy), including CYP3A5*3 reported by our group to be strongly associated with Doc toxicity. Methods: Germline SNPs were studied in participants who gave prospective consent for peripheral blood DNA genotyping. All subjects received Doc until unacceptable toxicity or progressive disease. From these, 399 subjects predominantly of Caucasian origin were analysed here. Toxicity grades 0-1 (controls; low toxicity) vs. grade > 2 (cases, high toxicity) were compared. Dominant genotypic model was assumed; Chi-square test with 10000 permutations were employed using SVS v8.3 and p < 0.05 considered statistically significant. Results: Each reported variant conferred risk. CYP3A5*3 allele (rs776746; OR 2.16 [1.18-3.96]), TNF-alpha (rs1800629), NAV1 (rs478472), NOS3 (rs1799983) were associated with fatigue. SNPs associated with myalgia were FACND2 (rs7637888), HIF1-alpha (rs11549465) and NDRG1 (rs2233335). XKR4 (rs4737264) showed association with peripheral neuropathy. SNPs in ABCC2, SLCO1B3 and VEGF-R1 genes showed associations with all three individual AEs tested. In a combined analysis of all the AEs, CYP3A5*3 allele retained significance (OR 1.9 [1.08-3.37]; as did IL1-beta (rs16944) and CYP2C8 (rs11572080). Conclusions: We confirm our previous finding that CYP3A5*3 genotype determines toxicity by its influence on Doc metabolism (EurJCancer 8(7),175,2010). NDRG1, FACND2 and XKR4, SNPs previously associated with paclitaxel-induced neuropathy, were now associated with Doc-induced myalgia or neuropathy. In conclusion, we report a subset of variants analysed conferring genetic predisposition to both paclitaxel and Doc AEs. The pleotropic drug effects on multiple genes/pathways appear to contribute to the overall phenotype of taxane toxicity.