Background: Fatigue, sleep problems, and depression are the most common behavioral symptoms experienced by breast cancer patients. The purpose of this study was to examine these behavioral symptoms’ impact on quality of life (QOL) for early stage breast cancer patients receiving radiotherapy (RT). Methods: This was a prospective study of 46 patients receiving whole breast RT (50 Gy plus a 10 Gy boost) following lumpectomy. Data were collected at pre-RT, week 6 of RT, and 6-weeks post-RT. QOL was measured by Short Form-36, fatigue by Multidimensional Fatigue Inventory, sleep by Pittsburgh Sleep Quality Index, depression by Inventory for Depressive Symptomatology-Self-Rated, and stress by Perceived Stress Scale. No patients were treated with chemotherapy. Demographic/clinical variables, including age, race, marriage, smoking history, hormone treatment, and cancer stage, were collected at the time of enrollment. Mixed effect modeling was utilized to observe behavioral symptoms’ impact on QOL over time. Results: Fatigue and depression, along with stress, had significant impact on QOL after controlling for body mass index (BMI; the only one significant demographic/clinical variable; see Table). Patients with more fatigue, depression, or stress were more likely to have worse QOL during and post-RT. Patients having a higher BMI at baseline also reported worse QOL over time. Sleep was significantly correlated with QOL in univariate analyses, while this effect disappeared in multivariate models. Conclusions: Behavioral symptoms, in particular fatigue and depression, along with stress, have significant impact on the QOL of early breast cancer patients’ receiving RT. Future research on the underlying biological mechanisms will improve our understanding of these symptoms and their relationships, which will help to find potential targets for multiple related symptoms and, ultimately, improve patients’ QOL.