Neuroprotection afforded by volatile anesthetic preconditioning (APC) has been demonstrated in both in vivo and in vitro experiments, yet the underlying mechanism is poorly understood. We therefore investigated whether suppression of p38 MAPK, NF-kappa B and the downstream pro-inflammatory signaling cascade contribute to sevofurane APC-induced neuroprotection. Male Sprague-Dawley rats were exposed for 30 min/day on 4 consecutive days to ambient air or to sevoflurane (1.2% or 2.4%). Then rats were subjected to filament occlusion of the middle cerebral artery (MCAO) for 60 min, and euthanized 3 days after MCAO for measuring infarct volume. APC with sevofurane markedly improved neurological performance of stroke rats, significantly decreased infarct volume, and robustly suppressed activation of NF-kappa B and p38 MAPK, and expression of inflammatory cytokines. Furthermore, APC with sevofurane showed a direct inflammation-suppressing effect in rat brain receiving intracerebroventricular infusion of a dose of LPS that doesn't cause overt brain damage. Thus, the data suggest that APC with sevoflurane confers neuroprotection against focal ischemic brain injury, at least in part, by the anti-inflammatory effects of sevoflurane.