Ischemic preconditioning is a phenomenon that describes how a sublethal ischemic insult can induce tolerance to subsequent ischemia. This phenomenon has been observed after focal or global ischemia in different animal models. However, the hypothesis that bacterial infection might lead to neuronal tolerance to injury has not been investigated. To mimic cerebral bacterial infection, we injected bacterial lipopolysaccharide (LPS) in the right dorsal hippocampus, followed 24 hours later by an excitotoxic lesion using kainic acid in the mouse model. Quantification of lesion size after cresyl violet counterstaining revealed that LPS pretreatment afforded neuroprotection to CA3 neurons against KA challenge. To investigate the events underlying this protection, we studied the cytokine profile induced after LPS injection. Interleukin (IL)-1β and transforming growth factor beta 1 (TGF-β1) were the main cytokines expressed at 24 hours after LPS injection. Because IL-1β has been described as deleterious in acute injury, we decided to investigate the function of TGF-β1. An adenovirus expressing a constitutively active form of TGF-β1 was injected intracerebrally 1 week before the induction of excitotoxic lesion, and neuronal protection was observed. To confirm the neuroprotective role of TGF-β1, the TGF-β1 adenovirus was replaced by recombinant human TGF-β1 protein and total neuroprotection was observed. Furthermore, the antibody-mediated blocking of TGF-β1 action prevented the protective effect of pretreatment with LPS. We have demonstrated in vivo that the cerebral tolerance phenomenon induced by LPS pretreatment is mediated by TGF-β1 cytokine.