Abstract Body fatness is an established risk factor for postmenopausal breast cancer, but it is unknown if this risk associated with excess body weight is reversible. We conducted a pooled analysis of 11 prospective studies in the Pooling Project of Prospective Studies of Diet and Cancer. Each study had adult body weight data at three time points, as well as follow-up for subsequent risk of breast cancer after the third weight measure. Weight change was assessed using reported or measured weight at baseline and two follow-up time points, each generally four to six years apart (over a total of ~10 years). Stable weight for each interval was defined as weight within 2kg of the previous weight. The referent group was women with stable weight (within 2kg) at all three time points across the 10-year period. Among 340,055 women, 10,427 breast cancers were diagnosed during follow-up. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) controlling for baseline body mass index (BMI), baseline physical activity, and postmenopausal hormone (PMH) use at the start of breast cancer follow-up, were estimated using proportional hazards regression on an aggregated dataset from all studies. Women who lost weight and kept the weight off, were at a lower risk of breast cancer than women with stable weight over the 10 years: >2.-4.5kg lost between baseline and the first follow-up body weight measure (n=482 cases): HR=0.92, 95% CI: 0.83-1.03; >4.5-9kg lost (n=283 cases): HR=0.86, 95% CI: 0.76-0.98; >9kg lost (n=95 cases): HR =0.81, 95%CI: 0.65-1.00). Women who initially lost weight (>2kg), but then re-gained it had a similar risk of breast cancer to those with stable weight over the same time period. When results were stratified by baseline age and BMI, there was no association between sustained weight loss and breast cancer among women younger than 50 years, nor those with a normal BMI (18.5-25 kg/m2) before weight loss. Among women who were aged 50 or more years and overweight or obese before the weight loss period, we observed a 21% lower risk of breast cancer for sustained weight loss of ≥4.5kg compared to women with stable weight over the same time period (n=245 cases, HR=0.79, 95% CI: 0.68-0.93). This observed association was driven by women who were not taking PMH (n=156, HR=0.71, 95% CI: 0.58-0.86). In this large, pooled prospective analysis of weight loss and breast cancer risk we found that losing 4.5 kg—and keeping it off—may lower breast cancer risk, particularly for women older than 50 who are overweight or obese. The results may provide motivation for women with elevated BMI to lose weight and potentially reduce their risk of breast cancer. Citation Format: Lauren R. Teras, Alpa V. Patel, Molin Wang, Bette J. Caan, Yu Chen, Avonne E. Connor, A. Heather Eliassen, Susan M. Gapstur, Mia M. Gaudet, Jeanine M. Genkinger, Graham G. Giles, I-Min Lee, Roger Milne, Norie Sawada, Howard D. Sesso, Meir Stampfer, Rulla Tamimi, Cynthia A. Thomson, Shoichiro Tsugane, Kala Visvanathan, Anne Zeleniuch-Jacquotte, Walter C. Willett, Stephanie A. Smith-Warner. Weight loss over 10 years of adulthood and subsequent risk of breast cancer: a pooled analysis of 11 cohort studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5311. doi:10.1158/1538-7445.AM2017-5311