Cancer-related fatigue (CRF), a prevalent symptom among cancer patients, is a side effect of external beam radiation therapy (EBRT). Even when targeting organs unrelated to caloric intake or the central nervous system, radiation therapy can increase CRF, a poorly understood toxicity resulting from patient-specific, systemic therapy-related, and radiation-specific factors. We sought to determine factors associated with fatigue among patients receiving EBRT for breast cancer.To determine the variables associated with fatigue among patients with nonmetastatic breast cancer, we retrospectively analyzed prospectively collected toxicity data for a cohort of 1286 adult females with breast cancer who began curative-intent EBRT between April 4, 2010, and October 10, 2017. We hypothesized certain variables are associated with provider-reported Common Terminology Criteria for Adverse Events version 4 fatigue, graded 0 to 3, at baseline and over the course of radiation treatment.All patients were women, with a median age of 57 (range, 24-90). Mean fatigue was low (0.35 [95% confidence interval, 0.32-0.38]) at the start of radiation, increasing weekly and peaking at week 6 (0.85 [0.81-0.90]). Baseline fatigue was associated with higher American Joint Committee on Cancer stage (P.001), N-stage (P.001), anxiolytics (P.001), anticonvulsants (P = .002), antidepressants (P = .006), antihistamines (P.001), and antipsychotics (P.001). Chemotherapy was not associated with baseline fatigue. Over the course of treatment, on multivariable analysis, only lower dose per fraction (P.001) was significantly associated with increasing fatigue. In a subgroup analysis, heart and lung mean, V5, and V20 doses were not found to be associated with increasing fatigue.This work informs clinicians which factors are associated with CRF at the start of radiation therapy (more advanced disease and prescription of anxiolytics, anticonvulsants, antidepressants, antihistamines, and antipsychotics) and increase CRF over the course of radiation (smaller fraction size). This extensive analysis of factors associated with fatigue provides further evidence that hypofractionated radiation therapy for breast cancer is associated with less acute toxicity than conventionally fractionated treatment.