Approximately 42% of the U.S. adult population is obese and data suggests that persons with obesity are at a 30% greater risk of developing colorectal cancer (CRC). Therefore, efficacious approaches to preventing and treating obesity will have significant effects on CRC incidence in the U.S. Although calorie restriction through lifestyle intervention is the most common approach to treat obesity, clinically meaningful weight loss is difficult to achieve via this method due to low adherence with calorie monitoring, indicating a need for innovation. Time-restricted eating, a type of intermittent fasting, has been shown in animals to impart cancer protective effects including lower body weight, decreased systemic inflammation, and improved glucose metabolism. Time-restricted eating is where individuals are asked to consume all their food for the day within a specified time frame, and water fast for the remaining hours of the day. We recently performed two short-term (≤12-weeks) pilot studies of time-restricted eating to evaluate its safety and preliminary efficacy on body weight and chronic disease risk markers in adults with obesity. Our results show the intervention is a safe and acceptable approach to weight loss among obese adults. Moreover, time-restricted eating produced approximately 3% weight loss from baseline and reductions in systolic blood pressure, oxidative stress and insulin resistance. Although these pilot findings show promise for time-restricted eating as an effective tool for CRC risk reduction among obese individuals, these data still require confirmation by a well powered longer-term clinical trial. The present proposal aims to implement a 12-month (6-month active weight loss phase, 6-month maintenance phase), controlled, parallel arm trial among 255 obese adults (45-65 years old) who are at elevated CRC risk. Subjects will be randomized to 1 of 3 groups: 1) Time-restricted eating (weight loss phase: daily ad libitum food intake from 11am – 7pm), 2) Calorie restriction (weight loss phase: daily 25% calorie restriction), or 3) Control (daily ad libitum food intake, no meal timing restrictions) to compare the effects on: (1) Body weight, body composition, and intervention adherence; (2) Circulating metabolic, inflammation, and oxidative stressrelated biomarkers; (3) Colonic mucosal gene expression profiles and mucosal inflammation, DNA damage and cellular growth; and (4) maintenance of benefits on body weight/composition and systemic/mucosal CRC risk markers. This proposal will be led by a transdisciplinary team with expertise in nutrition science, time-restricted eating, behavioral science, molecular markers of cancer, gastroenterology, and biostatistics. If the aims of this proposal are achieved, it will show for the first time that time-restricted eating can be implemented as a novel alternative to traditional dieting (i.e., daily calorie restriction) for weight control and CRC risk reduction in adults with obesity. The proposed study will also be the first and most comprehensive examination of molecular mechanisms that mediate the anticancer effects of time-restricted eating and calorie restriction.