The anorectic cobalt protoporphyrin (CoPP) is known to elicit short-term hypophagia and long-term weight loss through unknown mechanisms in the brains of experimental animals. The goal of this work was to determine 1) if the prolonged duration of action of CoPP is related to its prolonged retention within the brain and 2) utilizing immunohistochemical detection of Fos, the product of the early-immediate gene c-fos, which cells are activated following exposure to CoPP. These studies were carried out in male rats following intracerebroventricular administration of CoPP 0.4 µmol/kg body weight given under light halothane anesthesia. Residence of CoPP in the brain was determined by residual counts in dissected brains of ⁵⁷CoPP-injected rats. Fos immunoreactivity was mapped in coronal sections of rat brains 4-6 hours after injection with CoPP. The results showed that ⁵⁷CoPP was retained in the hypothalamus preferentially compared to the cortex of the brain and could be detected in the hypothalamus for in excess of 5 weeks. Fos activation was increased by CoPP, detected predominantly in neuronal rather than glial cells, and was markedly more robust in the hypothalamus than in other brain areas. Thus CoPP remains in the hypothalamus for prolonged periods and activates Fos expression in the hypothalamus.