The purpose of this study was to provide a rationale for 'chemotherapy-periodized' exercise by characterizing cyclical variations in fatigue and exercise response across a chemotherapy cycle and comparing exercise adherence during chemotherapy between a prescription that is periodized according to chemotherapy cycle length and a standard linearly progressed prescription.Women with breast cancer who were prescribed taxane-based chemotherapy were randomly assigned to a supervised aerobic and resistance exercise program following a chemotherapy-periodized exercise prescription (n=12) or to usual care during chemotherapy (n=15). Fatigue and steady state exercise responses were assessed in both groups prior to the first taxane treatment and across the third treatment (i.e., 0-3 days prior and 3-5 days after the third treatment, and 0-3 days prior to the fourth treatment) to assess cyclical variations. Adherence to the chemotherapy-periodized exercise prescription was compared to adherence to a standard linear prescription from a prior study in a similar population (n=51).Fatigue increased from baseline (marginal mean±standard error: 3.2±0.4) to prior to the third treatment (4.1±0.4, p=0.025), then peaked at 3-5 days after the third treatment (5.1±0.4, p=0.001), before recovering prior to the next treatment (4.3±0.5, p=0.021). The peak in fatigue at 3-5 days post-third treatment corresponded to a decrease in steady state exercise oxygen consumption (VO2) (p=0.013). Compared to a standard linear exercise prescription during chemotherapy, a chemotherapy-periodized exercise prescription resulted in higher attendance during the week after chemotherapy (57±30% vs 77±28%, p=0.04) and overall attendance (63+25% vs 78±23%, p=0.05).Fatigue and exercise VO2 vary across a chemotherapy cycle. A chemotherapy-periodized exercise prescription that accommodates cyclical variations in fatigue may increase adherence to supervised exercise.