The genetic obesity of the fa/fa rat is due to or accompanied by perturbances in the autonomic nervous control of different target tissues (e.g. endocrine pancreas, brown adipose tissue). These disorders are likely to be secondary to central dysregulation(s), which could lie somewhere within or in relationship with the hypothalamus. In view of the reported effects of CRF in stimulating sympathetic nerve-mediated mechanisms, while inhibiting vagus nerve-mediated ones, ovine CRF (oCRF) was administered for 7 days into the cerebral ventricles of fa/fa rats at a dose (5 μg/day) that did not affect the pituitary-adrenal axis. oCRF treatment stopped the excessive weight gain of the obese animals; oCRF-treated animals gained only 1 g over 6 days, while the vehicle-treated ones gained 29 g (P = 0.044). The oCRF effect was unrelated to changes in food intake, as the two groups were pair-fed. oCRF-treated obese rats were characterized by a decrease in basal hyperinsulinemia, increases in brown adipose tissue weight and activity, and decreases in hepatic glycogen content and epididymal fat pad weight. It is suggested that intracerebroventricular oCRF administration to obese fa/fa rats prevents the 10–15% increase in body weight observed in vehicle-infused obese rats within 1 week by modulating the impaired autonomic nervous control of different target tissues. This does not occur in lean rats (Endocrinology124: 733–739, 1989)