Ablation of the anteroventral third ventricle (AV3V) region, which includes the organum vasculosum laminae terminalis (OVLT), blocks the febrile response of guinea pigs to systemically injected endotoxin; by contrast, discrete lesions of the OVLT transiently enhance fever in rabbits and rats. To assess whether separate subdivisions of the AV3V may mediate these different effects, the thermal responses to Escherichia coli lipopolysaccharide (LPS, 0.25 μg/kg, i.v.) were measured in eight sheep before and 12–13 days after placement of lesions at various levels within the AV3V. The responses of four of these sheep to crude homologous endogenous pyrogen (EP, 1–2 mL, i.c.v.) were also evaluated. Additionally, five other sheep were tested with LPS 2–8 months postlesion. All the experiments were performed at thermoneutrality. Sheep were used because most of the frontal wall of their 3V forms an elongated OVLT consisting of an avascular body and a vascular base. The animals were classified postmortem according to the extent of tissue ablated. Lesion overlap analyses showed that (i) medial lesions which extended from the floor of the 3V to the anterior commissure and laterally into adjacent preoptic periventricular tissue were associated with significantly depressed fever after LPS (n = 2); (ii) comparable lesions, but which excluded the ventral portion of the AV3V, i.e., the base of the OVLT, did not alter the magnitude of the febrile response to LPS (n = 4); (iii) lesions of the lateral walls of the 3V and (or) of the adjacent medial preoptic and anterior hypothalamic areas but excluding the frontal 3V wall also did not affect fever height after LPS (n = 7). Damage to aspects of the walls of the lateral ventricles attenuated the febrile response to EP i.c.v. (n = 3). Hence, although no separate fever-inhibiting and fever-enhancing regions were found within the AV3V, these results indicate that the ventral portion of the AV3V, i.e., the vascular plexus of the OVLT, is critical for normal fever development in sheep.