Heat stroke (HS) is characterized by a systemic inflammatory response syndrome (SIRS) consisting of profound core temperature (T_c) changes in mice. Encephalopathy is common at HS collapse, but inflammatory changes occurring in the brain during the SIRS remain unidentified. We determined the association between inflammatory gene expression changes in the brain with T_c disturbances during HS recovery in mice. Gene expression changes of heat shock protein (HSP)72, heme-oxygenase (hmox1), cytokines (IL-1β, IL-6, TNFα), cyclooxygenase enzymes (COX-1, COX-2), chemokines (MCP-1, MIP-1α, MIP-1β, CX3CR1), and glia activation markers (CD14, aif1, vimentin) were examined in the hypothalamus (HY) and hippocampus (HC) of control (T_c~36.0ºC) and HS mice at T_c,Max (42.7°C), hypothermia depth (HD; 29.3±0.4°C) and fever (37.8±0.3°C). HSP72 (HY<HC) and IL-1β (HY only) were the only genes that showed increased expression at T_c,Max. HSP72 (HY<HC), hmox1 (HY<HC), cytokine (HY=HC), and chemokine (HY=HC) expression was highest at HD and similar to controls during fever. COX-1 expression was unaffected by HS, whereas HD was associated with ~3-fold increase in COX-2 expression (HY only). COX-2 expression was not increased during fever and indomethacin (COX inhibitor) had no effect on this T_c response indicating fever is regulated by other inflammatory pathways. CD14, aif1, and vimentin activation at HD coincided with maximal cytokine and chemokine expression suggesting glia cells are a possible source of brain cytokines and chemokines during HS recovery. The inflammatory gene expression changes during HS recovery suggest cytokines and/or chemokines may be initiating development or re-warming from hypothermia whereas fever pathway(s) remain to be elucidated.