We have previously shown that mild hypothermia applied after hypoxia-ischemia in newborn piglets and rats reduces brain injury evaluated 3-7 d after the insult. The aim of the present study was to assess the neuroprotective efficacy of hypothermia with respect to short- (neuropathology) and long-term (neuropathology and sensorimotor function) outcome after hypoxia-ischemia in 7-d-old rats. One hundred fourteen animals from 13 litters survived either 1 or 6 wk after a hypoxic-ischemic insult. The animals were randomized to either 1) normothermic recovery for the whole 1- or 6-wk period or 2) cooling to a rectal temperature of 32.0 degrees C for the first 6 h followed by normothermic recovery with the dam. Hypothermia offered a uniform protection of 27, 35, 28, and 25% in cerebral cortex, hippocampus, basal ganglia, and thalamus, respectively, in the 1-wk survivors (n = 32). The corresponding values for the 6-wk survivors (n = 61) were 22, 28, 37, and 35%. There was a significant correlation between sensorimotor performance and infarct volume (r = 0.66; p < 0.001). However, the sensorimotor function was not significantly improved by hypothermia if all animals were included, but in female pups the total functional score was higher in the hypothermia group (150 +/- 35 versus 100 +/- 34, p < 0.0007) which corresponded to a marked (51%) reduction of the neuropathology score in this subgroup. This is the first neonatal study to show a long-term histopathologic protection of the brain after posthypoxic hypothermia.