Previous studies from our laboratory suggested that adrenal hormones may participate, directly or indirectly, in the hypothalamic mechanism involved in the regulation of food intake. In the present studies, the effect of adrenalectomy on the development of gold thioglucose (GTG)-induced hyperphagia and obesity in mice was investigated. As expected, damage to the ventromedial hypothalamus by GTG was followed by hyperphagia and obesity. Ablation of the adrenal glands after the administration of GTG prevented the onset and development of hyperphagia and obesity. The administration of cortisone completely restored the hyperphagia and weight gain of GTG-treated adrenalectomized mice. The administration of desoxycorticosterone not only failed to restore the hyperphagia and obesity in these mice but, rather, led to a suppression of food intake, weight loss, and death. It is concluded that 1) GTG-induced hypothalamic hyperphagia and obesity are dependent on adrenal glucocorticoids, and 2) the ability of adrenal glucocorticoids to restore hyperphagia and obesity in hypothalamic lesioned adrenalectomized mice indicates that adrenal glucocorticoids can act on compounds outside of the ventromedial hypothalamus involved in the control of food intake.