ABSTRACT: PURPOSE:The aim of this study was to determine if there were any differences in health-related outcomes and physical activity (PA) between the two OptiTrain exercise groups and usual care (UC), 2 years post-baseline. METHODS:The OptiTrain study was a three-arm randomised controlled trial comparing 16 weeks of concurrent aerobic high-intensity interval training (HIIT) and progressive resistance exercise (RT-HIIT) or concurrent HIIT and continuous moderate-intensity aerobic exercise (AT-HIIT) to UC in 206 patients with breast cancer undergoing chemotherapy. Eligible participants were approached 2 years following baseline to assess cancer-related fatigue, quality of life, symptoms, muscle strength, cardiorespiratory fitness, body mass, PA, sedentary behaviour, and sick leave. RESULTS:The RT-HIIT group reported lower total cancer-related fatigue, (-?1.37, 95% CI -?2.70, -?0.04, ES?=?-?0.06) and cognitive cancer-related fatigue (-?1.47, 95% CI -?2.75, -?0.18, ES?=?-?0.28), and had higher lower limb muscle strength (12.09, 95% CI 3.77, 20.40, ES?=?0.52) than UC at 2 years. The AT-HIIT group reported lower total symptoms (-?0.23, 95% CI -?0.42, -?0.03, ES?=?-?0.15), symptom burden (-?0.30, 95% CI -?0.60, -?0.01, ES?=?-?0.19), and body mass -?2.15 (-?3.71, -?0.60, ES?=?-?0.28) than UC at 2 years. CONCLUSION:At 2 years, the exercise groups were generally experiencing positive differences in cancer-related fatigue (RT-HIIT), symptoms (AT-HIIT), and muscle strength (RT-HIIT) to UC. The findings provide novel evidence that being involved in an exercise program during chemotherapy can have long-term benefits for women with breast cancer, but that strategies are needed to create better pathways to support patients to maintain physical activity levels. TRIAL REGISTRATION:Clinicaltrials.gov registration number: NCT02522260. Trial registered on 9 June 2015. https://clinicaltrials.gov/ct2/show/NCT02522260 . Retrospectively registered.