Background: The development of paclitaxel-induced peripheral neuropathy (PIPN) is influenced by the age and genetic composition of patients. Paclitaxel is known to act as a substrate in SLCO1B3-mediated influx, ABCB1-mediated efflux from cancer cells, and CYP2C8-mediated metabolism. We conducted a prospective study to investigate whether age and these single nucleotide polymorphisms (SNPs) are correlated with PIPN. Methods: Breast cancer patients who received adjuvant weekly paclitaxel were genotyped for five SNPs in three genes, including rs4149117 in SLCO1B3; rs2032582, rs1045642, and rs1128503 in ABCB1; and rs10509681 in CYP2C8, using PCR quenching probe method. Clinical data, including the paclitaxel dose and onset and severity of neuropathy, were correlated with the genetic data. Results: We enrolled 127 Japanese patients with a median age of 50 years (range, 25–75 years). The mean total paclitaxel dose administered was 933 mg/m² (range, 560–960 mg/m²), and 85% received the full dose intensity treatment (960 mg/m² over 12 weeks). The majority of patients (98.4%) developed all grade neuropathy, and 51.9% of patients exhibited grade 2 or higher severity. Severe neuropathy, defined as those requiring a dose delay, dose reduction, or early termination of chemotherapy, occurred in 15.0% of patients. Of the five SNPs evaluated, the ABCB1 (rs1128503) TT genotype was associated with a grade 2 or higher neuropathy compared with the CC/CT genotype (p = 0.05). Of note, patients with the TT genotype aged > 60 years had a higher incidence of grade 2 or higher severity (p = 0.008) than those with the CC/CT genotype. Patients without PIPN were all wild type for the five SNPs. Patients aged > 60 years had a higher incidence of grade 2 or higher severity (p = 0.006) than younger patients, regardless of the SNPs. Conclusions: ABCB1 rs1128503 SNP and advanced age are correlated with PIPN. This findings may help clinicians determine which patients should avoid paclitaxel. Clinical trial information: UMIN000005294.