Chronic total sleep deprivation (TSD) of rats by the disk-over-water method reliably produces initial increases and subsequent decreases in waking intraperitoneal (Tip) and hypothalamic (Thy) temperatures, progressive increases in energy expenditure, skin lesions on the tail and plantar surfaces, debilitated appearance, and eventual death. We investigated the possible role of the preoptic/anterior hypothalamus (POAH) in the mediation of the TSD effects by comparing these effects in POAH-lesioned and unlesioned rats. Bilateral POAH lesions sufficient in size to impair homeothermic responses to changes in ambient temperature did not produce TSD-like temperature changes under baseline ambient temperatures of 28-29 degrees C, implying that the thermoregulatory changes produced by TSD do not result from impairment of the lesioned area. However, the possibility remains that the TSD effects are mediated by damage to POAH areas that were not lesioned. During TSD, lesioned and unlesioned rats showed similar progressive increases in energy expenditure, but the lesioned rats showed earlier, steeper, and eventually greater declines in Tip and Thy. This result suggests that in unlesioned rats the POAH may counter-regulate against, and thereby attenuate, the reduction in heat retention caused by TSD. This failure of regulation in lesioned rats is consistent with their impaired response to ambient temperature change and implies that, in unlesioned rats, some POAH thermoregulatory mechanisms continue to function normally during TSD. Lesioned rats did not show the characteristic TSD-induced early increases in Tip and Thy. This result could imply either that heat retention was so compromised that body temperatures did not rise in spite of a TSD-induced increases in thermoregulatory setpoint, or that the setpoint increase in unlesioned rats is POAH-mediated. Notwithstanding the greater Tip and Thy declines in lesioned rats, they survived the TSD procedure longer than the unlesioned rats, thus supporting previous indications that death did not result from hypothermia.