Abstract Obesity is a known risk factor for colorectal cancer, but the influence of weight change during one's lifetime on colorectal adenoma, precursor to colorectal cancer, is less understood. We prospectively investigated the association between weight change in different time periods in adulthood and the risk of colorectal adenoma. We included 1,041 incident distal colorectal adenoma cases (negative on baseline trial flexible sigmoidoscopy screen and positive on follow-up trial sigmoidoscopy screen 3-5 years later) and 16,394 controls (negative on both trial screens) from the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We required participants to have no history of colorectal polyps, other colon comorbidities or cancer. Using self-reported weight data at trial baseline, we estimated odds ratios (OR) and 95% confidence intervals (95% CI) for early-late (age 20-baseline, i.e. ages 55-74), early-middle (age 20-50) and middle-late (age 50-baseline) adulthood weight change with colorectal adenoma using logistic regression. We defined the weight stable group (referent) as weight loss <0.5 kg/5 years or weight gain ≤1 kg/5 years. We defined the weight loss group as those who lost ≥0.5 kg/5 years. We included three weight gain groups: >1 to ≤2, >2 to ≤3 and >3 kg/5 years. We adjusted models for starting BMI (age 20 or 50), age, sex, race, smoking and other factors including diet. Compared to weight stable participants, weight loss in early-late adulthood was inversely associated with colorectal adenoma (OR=0.6, 95% confidence interval (CI): 0.3-0.9); results were similar for early-middle adulthood (OR=0.5, 95% CI: 0.3-0.8), but less pronounced for middle-late adulthood (OR=0.8, 95% CI: 0.7-1.0). Early-late adulthood weight gain of >3 kg/5 years was associated with higher odds of adenoma (OR=1.3, 95% CI: 1.1-1.6); results were similar for middle-late adulthood (OR=1.2, 95% CI: 1.0-1.4), but less pronounced for early-middle adulthood (OR=1.1, 95% CI: 0.9-1.3). We observed some evidence of a stronger association for men than women (for early-late adulthood weight gain >3 kg/5 years, OR for men=1.4, 95% CI: 1.1-1.8; OR for women=1.1, 95% CI: 0.8-1.5), although the interaction was not statistically significant (p-int=0.65). When we stratified by starting BMI, we observed a significantly decreased risk of colorectal adenoma with weight loss from early-late adulthood among those who were overweight/obese at age 20 (OR=0.4, 95% CI: 0.2-0.9). Findings suggest that weight loss in adulthood for those who are overweight/obese is associated with a reduced risk of colorectal adenoma. In addition, our results suggest that a modest rate of weight gain in adulthood of >3 kg/5 years is associated with an increased risk of colorectal adenoma. These findings underscore the importance of healthy weight maintenance in adulthood in preventing colorectal adenoma. Citation Format: Shisi He, Sonja I. Berndt, Andrew T. Kunzmann, Cari M. Kitahara, Wen-Yi Huang, Kathryn Hughes Barry. Weight change in adulthood and colorectal adenoma incidence in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-158.