Given the increasing prevalence of and severity of complications associated with obesity, there is great need for treatments resulting in prolonged weight loss. Long-term maintenance of weight loss requires sustained changes in food-intake and energy-expenditure strategies, which are unfortunately often taxing, resulting in a return to predieting weight. Therefore, drug therapies may facilitate greater adherence to a restricted diet and prolong weight loss. One such drug is rapamycin (RAP), a mechanistic target of rapamycin (mTOR) inhibitor. Here, we show that a single injection of RAP dampens the hyperphagic response in calorically restricted rats when they are returned to free feed immediately or 10 days after injection. Moreover, we demonstrate that a single injection of RAP given to calorically restricted rats prevents body-weight regain when animals are returned to free feed either immediately or 10 days after injection. Furthermore, we extend our previous findings that RAP does not produce malaise or illness and show that RAP does not produce any behavioral deficits that may inhibit an animal from eating. Thus, we suggest that mTOR may be a useful target in obesity research, given that its inhibition may decrease the hyperphagic response following caloric restriction. (PsycINFO Database Record (c) 2019 APA, all rights reserved).