Fatigue is a frequent problem during and after cancer treatment. We investigated different courses of fatigue from pre-diagnosis, through therapy, to long-term survivorship and evaluated potential implications on long-term quality of life (QoL). Breast cancer patients diagnosed in 2001-2005 were recruited in a case-control study in Germany (MARIE). At follow-up in 2009 (median 5.8years, MARIEplus), patients self-reported current fatigue and QoL status using validated questionnaires (FAQ, EORTC QLQ-C30). In addition, survivors retrospectively rated fatigue levels pre-diagnosis, during different treatment phases, and 1year post-surgery. Our analyses included 1,928 disease-free cancer survivors and comparisons with fatigue and QoL scores from the general population. Fatigue levels were substantially increased during chemotherapy and radiotherapy. Among patients who received both therapies, 61.4% reported higher, 30.0% same, and 8.6% lower fatigue levels during chemotherapy compared to radiotherapy. Courses of fatigue varied widely between individuals. Survivors with persisting long-term fatigue had significantly and markedly worse scores for all QoL functions and symptoms about 6years post-diagnosis than other survivors and compared to the general population. Survivors without substantial fatigue post-treatment had QoL scores largely comparable to the general population. DISCUSSIONS/CONCLUSION: Chemotherapy appears to have a stronger impact on fatigue than radiotherapy. Breast cancer survivors may experience long-term QoL comparable to the general population, even when suffering from substantial fatigue during treatment. Yet, persistent fatigue post-treatment may lead to extensive long-term loss in QoL concerning physical, social, cognitive, and financial aspects. Fatigue management should be obligatory during and post cancer treatment.