Background: N-myc downstream regulated gene (NDRG)-1 has been implicated in Charcot Marie Tooth disease, a peripheral nerve hereditary disorder and in the development and maintenance of the myelin sheath. We hypothesize that NDRG-1 may be implicated in paclitaxel-induced peripheral neuropathy. Methods: Breast cancer patients who received adjuvant weekly paclitaxel were genotyped for 10 single nucleotide polymorphisms (SNPs) in 9 genes, including rs2233335 in NDRG-1 using MassArray (Sequenom) technology. Immunohistochemical (IHC) staining of NDRG-1 was performed on normal nerve tissue in archival lumpectomy/mastectomy specimens. Clinical data including paclitaxel dose intensity and density, onset and severity of neuropathy was correlated with genetic and IHC data. Results: Of the 122 patients that were evaluated, 67% were Chinese, median age was 51 (26 – 79) years and 9% had diabetes. Mean total paclitaxel dose administered was 924 (240 – 960) mg/m². Median duration of treatment was 12 (3 – 18) weeks, with 36% completing full dose intensity (960mg/m² in 12 weeks). 57.4% developed all grade neuropathy, with 20.5% having ≥grade 2 severity. Severe neuropathy, defined as those requiring dose delay, dose reduction or early termination of chemotherapy, occurred in 9.8%. Expectedly, presence of diabetes correlated with severe neuropathy (36% vs 7%; p=0.01). Of the 10 SNPs evaluated, NDRG-1 (rs2233335) CC/CA genotype was significantly associated with severe neuropathy compared to the AA genotype (28% vs 7%, p=0.016). Of note, patients with the CC/CA genotype and who were younger than 50 years of age had a higher incidence of ≥grade 2 (80% vs 14%, p=0.005) and severe neuropathy (80% vs 6%, p=0.001) than those with the AA genotype. Patients with severe neuropathy were more likely to stain negative for NDRG-1 in nerve tissues compared to those who had no neuropathy (80% vs 0%, p=0.047). Conclusions: Absence of NDRG-1 expression on nerve tissue and NDRG-1 rs2233335 SNP is associated with paclitaxel-induced severe neuropathy, and may guide selection of patients who should avoid paclitaxel. Correlation of NDRG-1 SNP with expression and functionality requires further study.