Background: Physical inactivity is a modifiable risk factor for breast cancer recurrence, but estimates suggest at least 50% of breast cancer survivors are insufficiently active. Guidelines specify all cancer survivors should avoid inactivity, and 90-minutes of moderate-vigorous physical activity (MVPA) per week is associated with clinically meaningful benefits (e.g., reduced cancer-related fatigue). Among the general population, how people feel during exercise (i.e., “affective response to exercise”) predicts future exercise engagement. Past work shows prescribing affect-regulated exercise can increase MVPA among inactive adults; however, this strategy has yet to be tested with cancer survivors. The overarching goal of this trial-in-progress is to test the hypothesis that an affect-regulated exercise prescription (Affect-Rx) can promote clinically meaningful increases in MVPA among inactive breast cancer survivors. Methods: Design: The Obesity-Related Behavioral Intervention Trials (ORBIT) model was used to inform all choices about design and key research milestones for two sequential studies. Study 1 (Phase Ib) is a stakeholder-centered, single-arm pilot trial (NCT04903249). Study 2 (Phase IIa) is a randomized (2:1) proof-of-concept trial. In both studies, MVPA will be measured using waist-worn ActiGraph wGT3X-BT accelerometers for 10 days at baseline, 2-, 6- and 12-weeks follow-up. Participants also complete brief ecological momentary assessments (EMAs) of their feeling states (e.g., pain, fatigue) three times per day for the same 10-day data collection periods. Participants: >18 years or older, physically inactive, stage 0-III breast cancer survivors, with primary cancer-treatment completed within the last 5-years. Intervention: Both studies deliver the Affect-Rx prescription: Exercise at the highest pace that still feels good. The Control condition in Study 2 is a heart-rate regulated exercise prescription. Endpoints and Planned Analyses: The goal of Study 1 is to refine the study protocol for acceptability via participant interviews and objective indicators of acceptability (e.g., accelerometer wear-time). The primary milestone for Study 1 is a fixed protocol ready for testing in Study 2. The goal of Study 2 is to quantify the effect of Affect-Rx on MVPA at 12-weeks relative to Control. The primary milestone for Study 2 is clinically meaningful impact on MVPA operationalized as >50% participants completing 90-minutes of MVPA at the end of 12 weeks. The associations between daily variability in feeling states and MVPA will be analyzed using a mixed-effects, hierarchical regression modeling approach. Current Enrollment: Data collection for Study 1 are ongoing. To date, N = 37 women have enrolled in Study 1 and data collection is complete for N = 13 at week-12. We aim to collect complete data from at least N = 20 women in Study 1 and N = 60 women in Study 2. Clinical trial information: NCT04903249.