Background: Cancer-related fatigue (CRF) is a common and distressing symptom of cancer and/or cancer treatment that persists for years after treatment completion in approximately one third of cancer survivors. Exercise is beneficial for the management of CRF, and general exercise guidelines for cancer survivors are available. There are multiple potential pathways by which exercise improves CRF, and cancer survivors with CRF are diverse with respect to cancer type, treatments and experienced side effects. While the general exercise guidelines are likely sufficient for most cancer survivors, tailoring of exercise interventions may be more effective in those with persistent fatigue. The primary aim of this research is to investigate the effect of a traditional vs. tailored exercise intervention on CRF severity in cancer survivors with persistent CRF. Methods/design: Cancer survivors (≥ 3 months and ≤ 5 years since primary treatment) who score ≤ 34 on the Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-F) will be randomly allocated to one of two parallel treatment arms: traditional (active control) and tailored exercise. Participants in the traditional exercise group will engage in aerobic and resistance exercise that is consistent with exercise guidelines for cancer survivors. The tailored exercise group will be prescribed an intervention designed to address individual deficits identified at baseline, such as loss of muscular strength, cardiorespiratory deconditioning or sleep disturbance. Participants will be assessed before and after the intervention for CRF severity and other patient-reported outcomes, neuromuscular function and fatigue in response to whole-body exercise, sleep quantity and quality, physical activity levels, cardiorespiratory fitness and blood biomarkers. Discussion: To our knowledge, this will be the first study to compare the effects of a traditional vs. tailored exercise intervention on CRF severity in cancer survivors with persistent CRF. Using physiological, behavioural and patient-reported outcomes, this study will add to the current knowledge about both the factors contributing to CRF, and the potential reduction in CRF severity with an exercise intervention. Trial registration: The study is registered at ClinicalTrials.gov ( NCT03049384 ), February, 2017.