Calorie restriction regimens are popular for their purported health-promoting effects. However, it is unclear whether chronic reduction in energy intake and subsequent weight loss have beneficial effects in the absence of obesity. To this end, the results of studies that examined the effects of the same diet-induced weight loss in individuals with and without obesity were reviewed. The contribution of lean mass to the total amount of weight lost is greater in participants without obesity than in those with obesity, but the reductions in resting, nonresting, and total energy expenditure are of similar magnitude. Both in the presence as well as in the absence of obesity, weight loss decreases visceral adipose tissue and liver fat, increases insulin sensitivity in skeletal muscle (insulin-mediated whole-body glucose disposal rate) and in adipose tissue (meal-induced or insulin-induced suppression of plasma free fatty acid concentration), and augments insulin clearance rate, without affecting pancreatic insulin secretion. These effects are of similar magnitude in participants with and without obesity and result in reductions in fasting plasma glucose and insulin concentrations. These data suggest that the same degree of calorie restriction and the same amount of weight loss have multiple beneficial effects on health outcomes in individuals without obesity, similar to those observed in individuals with obesity.