The effect of the dietary macronutrient composition on weight loss has been a controversial issue for decades. During that time, a high-protein, high-fat, and low-carbohydrate diet has been one of the more popular weight loss diets with the public. We hypothesized that a computer simulation model using STELLA software could help to better understanding the effect of the dietary macronutrient composition on weight loss. We calculated daily total oxidation instead of total energy expenditure as others have done based on the facts that carbohydrate, fat, and protein intake influence carbohydrate, fat, and protein oxidation. In order to create a simple and accurate model comparing dietary macronutrient composition effects, we eliminated exercise as a factor and focused on a sedentary population. The model was validated by five sets of published human data. Following model validation, simulations were carried out to compare the traditional high-carbohydrate diet recommended by the American Dietetic Association and two well-known high-protein diets (Atkins and the Zone diet). The results of computer simulation suggested that the lean tissue retention effect of a high-protein diet, especially with a lower-fat diet, compared with a traditional high carbohydrate diet over 6 months.