Data indicate that bacterial products in combination with other antenatal or postnatal exposures increase the risk of perinatal brain injury. We have previously shown that administration of lipopolysaccharide (LPS) 4 h before hypoxia-ischemia (HI) increases brain injury in 7-d-old rats. The mechanisms behind such sensitization are unclear, but contrasts against a preconditioning effect of LPS given 1-3 d before ischemia in adult animals. To investigate how the effects of LPS depend on the time interval between administration and HI in the developing brain, we evaluated the effect of varying time interval (2-72 h) between LPS and HI, the duration of HI (20 or 50 min), and age of the rat pups (postnatal d 4 or 7). Outcome was assessed by brain injury scoring of specific regions. We found that LPS reduced brain injury (by 78%) when administered 24 h before 50 min of HI. However, when LPS was administered 6 h before either 20 or 50 min of HI, brain injury was increased by 2026% and 137%, respectively. Even LPS given 72 h before HI increased injury, both when LPS was administered at postnatal d 4 (by 446%) and 7 (by 77%). In conclusion, LPS enhanced vulnerability in the developing brain both in the acute (4-6 h) and the chronic (72 h) phase after administration, whereas an intermediate interval between LPS and HI had the opposite effect. The long-term sensitizing effect of LPS has not been previously described.