The obesity which follows destruction of the ventromedial nucleus (VMN) of the hypothalamus of rats is accompanied by hyperphagia and hypersecretion of insulin. The effects of weight gain after ventromedial lesions were examined after hypophysectomy, after adrenalectomy and in rats in which the secretory function of the (3-cells had been destroyed with streptozotocin. Mature female rats received streptozotocin (65 mg/kg) intravenously: a) prior to hypothalamic injury; b) 7 days following hypothalamic injury; or c) after the rats had already become obese following hypothalamic damage. Weight gain of lesioned rats was not impaired by hypophysectomy or adrenalectomy. Treatment of lesioned-hypophysectomized rats with growth hormone prevented most of the increase in weight. Cortisone treatment of adrenalectomized rats with lesions had no significant effect. Both lesioned and control rats lost weight following treatment with streptozotocin until supplemental insulin was given. Body weight of all animals was maintained by daily injection of insulin (1 U/100 g body weight). With a dose of 2 U/100 g, body lesioned and control diabetic rats gained weight at similar rates. Food intake varied with the dosage of insulin in both lean diabetic and hypothalamic injured diabetic rats. Increasing insulin doses increased food intake and weight gain in both lean and VMN rats. The identical response of streptozotocin-treated control and VMN lesioned rats to insulin suggests that the obesity which follows hypothalamic damage results directly from a hypersecretion of insulin which in turn induces a secondary hyperphagia. (Endocrinology90: 885, 1972)