The effects of adrenalectomy on food intake, weight gain, plasma glucose, and corticosterone levels were investigated in normal untreated controls and gold thioglucose-(GTG) treated hyperphagic obese mice. Adrenalectomy of normal untreated mice was followed by a transient reduction in food intake and body weight with a return, after approximately 7 days, to levels which paralleled those of untreated sham-operated mice. Plasma corticosterone levels were significantly depressed in all untreated adrenalectomized mice. Plasma glucose levels were not affected by adrenalectomy. In sharp contrast to the response of untreated adrenalectomized mice, adrenalectomy of GTG-treated hyperphagic obese mice was followed by a sudden and persistent drop in food intake (anorexia) and body weight. These mice were unable to maintain their body weight. Despite this condition, the mice did not appear to be physically debilitated until a short time (6-12 h) before their death which was preceded by a period of severe hypoglycemia. These findings indicate that the hyperphagia and weight gain of GTG-treated obese mice is dependent on adrenal hormones. The anorexia after adrenalectomy of GTG-treated hyperphagic obese mice may be the result of a direct dependence of central or peripheral structures involved in the regulation of food intake on adrenal hormones. Alternatively, these structures may be affected by the action of metabolites or hormones which arise as a consequence of adrenal insufficiency.