Endogenous pyrogen (EP), injected systemically or intracerebrally, evokes fever and certain changes in plasma trace metal and glycoprotein levels which are characteristic of the acute-phase reaction. It is generally assumed that EP enters the brain from the blood, although it has not yet been demonstrated that EP crosses the blood-brain barrier (BBB). The possibility that EP might penetrate the brain through the organum vasculosum laminae terminalis (OVLT), which is outside of the BBB and located in close proximity to the medial preoptic region (MPO, the primary site sensitive to locally applied EP), was investigated by making electrolytic lesions (3 mA, 20 sec, anodal) in the anteroventral wall of the third ventricle of guinea pigs (AV3V-X). After 10 days, their febrile and selected acute-phase responses (plasma iron, zinc, copper, and sialic acid levels) to endotoxin (LPS, S. enteritidis, 2 μg/kg, IP), which induces EP production by the host, were measured; controls were sham-operated guinea pigs. LPS did not induce in the AV3V-X animals either fever or rises in plasma copper and sialic acid levels; however, as in the controls, it caused hypoferremia and hypozincemia. To exclude damage to the MPO as a cause of these responses, sham and AV3V-X guinea pigs were administered homologous EP intrapreoptically (1 μ1 bilaterally). Comparable fevers developed in both groups of animals. Hence, the integrity of the AV3V region including the OVLT seems to be critical for the EP-induced elevations of both body temperature and plasma levels of acute-phase proteins, but not for the fall of plasma iron and zinc levels. It may be that EP passes into the brain through the OVLT. © 1983.