The fate of the metabolic regulatory protein leptin was studied after intracerebroventricular (i.c.v.) administration into the lateral ventricle of the brain. In the brain, a mean of 72% of the recovered radioiodinated leptin was intact. Efflux from the brain for leptin occurred with the reabsorption of the cerebrospinal fluid into the blood. Leptin appearing in the blood was 71% intact over the course of the study. The amount of leptin in the blood rose slowly, and 20 min after i.c.v. injection equaled or exceeded levels previously seen 20 min after i.v. administration. Autoradiography showed the slow disappearance of leptin from the ventricular system over time. The degree of periventricular penetration of radiolabeled leptin also was determined. By 30 min, leptin was detected 600 microm from the midline, but computer-assisted image analysis showed that the amount of radioactivity had fallen to half the midline value by 300 microm. The concentration of leptin within the arcuate nucleus, previously observed after i.v. administration, was not seen after i.c.v. injection. High concentrations of leptin were found at the choroid plexus, suggesting the presence of leptin receptors on the brain side of the blood-cerebrospinal fluid barrier and within the lumen of the middle cerebral arteries.