We reported previously that adrenalectomy reduced the energy density of body weight gain (an indicator of proportional gain in lean and fat tissue) and the efficiency of energy retention in obese (ob/ob) mice to values approximating those in lean mice, but that adrenalectomy had much less influence on these parameters in ob/ob mice fed a purified high fat diet. To determine if fat was the exclusive factor in the purified high fat diet that negated effects of adrenalectomy, ob/ob mice were fed a purified high carbohydrate (glucose) diet identical in composition to the high fat diet, except for the fat/carbohydrate ratio. Responses of adrenalectomized ob/ob mice fed the purified high glucose diet from 4 to 7 wk of age mimicked those of mice fed the purified high fat diet, not those of mice fed the high carbohydrate nonpurified diet. Plasma glucose responses to a glucose load in adrenalectomized ob/ob mice paralleled the diet-dependent changes in energy balance. These results demonstrate that diet composition interacts with adrenal secretions to influence energy and glucose metabolism in ob/ob mice; consumption of either a purified high glucose or high fat diet negates the beneficial effects of adrenalectomy on energy and glucose metabolism observed when adrenalectomized ob/ob mice consume a nonpurified diet.