© 2018 The Authors. Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS) Objective:: Despite the known health benefits of weight loss among persons with obesity, observational studies have reported that cycles of weight loss and regain, or weight cycling, are associated with increased mortality. To study whether weight loss must be sustained to achieve health and longevity benefits, we performed a randomized controlled feeding study of weight cycling in mice. Methods:: In early adult life, obese mice were randomized to ad libitum feeding to sustain obesity, calorie restriction to achieve a “normal” or intermediate body weight, or weight cycling (repeated episodes of calorie restriction and ad libitum refeeding). Body weight, body composition, and food intake were followed longitudinally until death. A subsample of mice was collected from each group for determination of adipose cell size, serum analytes, and gene expression. Results:: Weight loss significantly reduced adipose mass and adipocyte size in both sexes, whereas weight cycling animals regained body fat and cell size during refeeding. Sustained weight loss resulted in a dose-dependent decrease in mortality compared with ad libitum feeding. Conclusions: Weight cycling significantly increased life-span relative to remaining with obesity and had a similar benefit to sustained modest weight loss.