Background: Cancer related fatigue (CRF) is commonly reported among breast cancer survivors and can negatively impact quality of life and treatment adherence. Large, prospective, longitudinal studies assessing CRF in breast cancer survivors compared to matched non-cancer controls are rare. Methods: Breast cancer survivors (n = 581, stage I-IIIBC, mean age 53.4) from community oncology clinics and age-matched controls (n = 364, mean age 52.6) completed the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI, scores range -24 to 96) prior to chemotherapy (T1), at chemotherapy completion (T2) and six-months after chemotherapy (T3). Linear mixed models compared trajectories of CRF over time in survivors compared to controls, adjusting for age, education, race, BMI, marital status, menopausal status, and depressive symptoms. Results: Survivors reported greater CRF compared to controls at all time points (mean total score T1 9.4 vs. -3.7, T2 17.0 vs. -3.3, and T3 8.5 vs. -3.1, all p < 0.001; all subscales p < 0.001). From T1 to T2 survivors experienced a significant increase in CRF as shown in the total score (mean change (MC) = 8.3; effect size (ES) = 0.4 , p < 0.001), and general, mental, and physical sub-scales (MC = 4.3, 2.1, 3.2 , ES = 0.7, 0.5, 0.7, respectively, all p < 0.001), while controls experience minimal changes (MC = 0.1-0.3, ES < 0.09, p > 0.05). At T3 survivors total score returned to T1 values (MC = -0.1, ES = 0.01, p = 0.461), which was, however, still greater than controls ( p < 0.001), while general, mental, and physical CRF subscale scores remained significantly higher than T1 values (MC = 1.2, 1.7, 1.9, ES = 0.2, 0.4, 0.3, respectively, all p < 0.001; controls no change). Group by time interactions indicated changes over time were greater in the survivors than controls (p < 0.001). In multivariate analyses of survivors, age, BMI, performance status, and baseline depression significantly predicted change in CRF. Conclusions: These results from the largest well-controlled study to date showed that breast cancer survivors experience significantly more CRF prior to and after chemotherapy compared to healthy controls. Further research should aim to identify subgroups of survivors most susceptible to CRF.