The effect of varying dietary macronutrient content on the body composition of AKR/J and SWR/J mice was examined. Dietary fat was fed at three levels (45, 30, and 15 kcal%), while dietary protein also was varied across three levels (10, 20, and 30 kcal%). All mice were placed on the defined diets at 5 wk of age and maintained on these diets for 12 wk. AKR/J mice were significantly larger and had a significantly greater carcass fat content compared with SWR/J mice in all dietary conditions. There was a clear dose-response effect of dietary fat on body fat in the AKR/J mice. In contrast, SWR/J mice showed an increase of body fat only when fed the diet containing the highest level of dietary fat and the lowest protein concentration. High levels of dietary protein (30 kcal%) resulted in a significant decrease of carcass fat in the AKR/J mice compared with diets containing either 20 or 10 kcal% protein. This effect of protein was not observed in the SWR/J mice except in the groups fed the 45 kcal% fat diets. These findings demonstrate a strong interaction of genetic background and macronutrient content of the diet on body composition. The AKR/J strain of mouse has a greater percentage of carcass fat and is more responsive to the effects of dietary fat composition compared with the SWR/J strain.