Background: Obesity is a growing health problem in the Unites States and around the world. Excess body weight has been linked to both an increased risk of developing breast cancer and poor prognosis in women diagnosed with early stage disease. A recent meta-analysis of 82 studies demonstrated that risk of breast cancer mortality was increased by 35% in women who were obese at the time of breast cancer diagnosis compared to women who were of normal weight. The Breast cancer Weight Loss (BWEL) study will evaluate the effect of weight loss after breast cancer diagnosis on risk of cancer recurrence. Methods: BWEL is a Phase III randomized trial evaluating the impact of a telephone-based weight loss intervention vs control on invasive disease-free survival (iDFS) in 3136 overweight and obese women with Stage II-III breast cancer. Eligibility criteria include diagnosis of hormone receptor positive or triple negative breast cancer within the preceding 12 months, body mass index of ≥27kg/m², and completion of surgery, chemotherapy, and radiation (if administered). Participants are randomized to a 2-year telephone- and mail-based weight loss intervention, adapted from the Diabetes Prevention Program, plus a health education program or to a health education alone control group. The study has 85% power, using a one-sided Type I error rate of 0.025, to detect a hazard ratio of 0.80 between groups. This equates to a 4.1% absolute reduction in iDFS events in the intervention group vs. controls. Secondary aims will evaluate the impact of the weight loss intervention upon overall survival, weight and body composition, and patient-reported outcomes. Fasting blood is collected serially over time, and tissue samples of malignant and benign breast tissue are collected at baseline to provide insight into the biologic mechanisms linking obesity and breast cancer. BWEL opened in September 2016. To date, 1015 patients have been randomized and more than 1100 sites in the US and Canada have activated the trial. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180868, U10CA077202. Clinical trial information: NCT02750826