To determine the effect of pre-hypoxic-ischemic (HI) hypo and hyperthermia on neuropathologic outcome in the immature brain, groups of 7-day rat pups underwent unilateral common carotid artery ligation and exposure to hypoxia in 8% oxygen at 37 degrees C for 3 h. Prior to HI, rat pups were divided into three groups and received either: (a) 3-1 h periods, at 8-h intervals, 24 h prior to HI, (b) 1-3 h period, 24 h prior to HI, or (c) 1-3 h period, immediately prior to HI, of exposure to environmental temperatures of 28 degrees C, 31 degrees C, 34 degrees C, 37 degrees C, or 39 degrees C. Following HI, all animals were returned to their dams for neuropathologic assessment at 30 days of age. Mortality was highest among those animals exposed to pre-HI hypothermia at 28 degrees C. Only those animals who were pre-conditioned with hyperthermia at either 37 degrees C or 39 degrees C, immediately prior to HI, displayed a significant reduction in brain damage compared to control (p<0.01). These results indicate that hyperthermia induced prior to HI protects the immature brain from damage. This study further emphasizes the importance of a cautionary approach in implementing systemic hypothermia during clinical trials, and the need to further understand the timing and effects of thermoregulation on the immature brain.