Exposure to preconditioning (PC) hypoxia 24 h before a severe hypoxic-ischemic (HI) insult reduces development of injury in the immature brain. Several protective regimens have proved effective in the short-term but not in the long-term perspective. The aim of the present study, therefore, was to evaluate the PC effect on long-term morphologic and neurologic outcome in the developing brain. Six-day-old rats were subjected to hypoxia (36 degrees C, 8.0% O2; PC/HI group) and sham controls to normoxia (36 degrees C; HI group) for 3 h. Twenty-four hours later, all rats were exposed to cerebral HI produced by unilateral carotid artery occlusion combined with 1 h, 15 min of hypoxia (36 degrees C, 7.7% O2). A cylinder test was used to evaluate forelimb asymmetry to determine sensorimotor function at 4, 6, and 8 wk of age. Spatial/cognitive ability was assessed by Morris water maze trials at 7 wk of recovery. Neuropathologic analysis was performed 8 wk after insult. Brain damage was reduced (p<0.0001) in PC/HI (45.0+/-11.1 mm3) in comparison with HI (159.3+/-12.2 mm3) rats. A bias for using the ipsilateral forelimb in wall movements was observed in the cylinder test in HI compared with PC/HI rats at 4 (p<0.001), 6 (p<0.01), and 8 (p<0.0001) wk of age. Results of the Morris water maze test revealed differences (p<0.0001) in average path length between groups on the third and fourth day of trials. Hypoxic PC before HI reduced brain injury by 72% at 8 wk after the insult and provided long-term improvement of sensorimotor and spatial/cognitive functions.