Women with breast cancer frequently report distressing symptoms during and after treatment that can significantly erode quality of life (QOL). Symptom burden among women with breast cancer is of complex etiology and is likely influenced by disease, treatment, and environmental factors as well as individual genetic differences. The purpose of the present study was to examine the relationships between genetic polymorphisms within Neurotrophic tyrosine kinase receptor 1 (NTRK1), Neurotrophic tyrosine kinase receptor 2 (NTRK2), and catechol-O-methyltransferase (COMT) and patient symptom burden of QOL, pain, fatigue, anxiety, depression, and sleep disturbance before, during, and after treatment for breast cancer in a subset of participants (N = 51) in a randomized clinical trial of a novel symptom-management modality for women with breast cancer undergoing chemotherapy. Patients were recruited at the time of initial breast cancer diagnosis and completed all survey measures at the time of recruitment, after the initiation of treatment (surgery and/or chemotherapy), and then following treatment conclusion. Multiple linear regression analyses revealed significant associations between NTRK2 and COMT single nucleotide polymorphism (SNP) genotype and symptom burden. Two COMT variants were associated with the specific symptoms of anxiety and QOL measures prior to the initiation of chemotherapy as well as pain interference and severity during and after treatment. Genotype at the NTRK2 SNP rs1212171 was associated with both sleep disturbance and fatigue. These findings, while exploratory, indicate that the genotypes of NTRK2 and COMT may contribute to relative risk for symptom burden during and shortly after the period of chemotherapy in women with early stage breast cancer.