Sevoflurane preconditioning has recently been demonstrated to protect ischemic brain in vivo and in vitro. However, mechanisms underlying this neuroprotection have not been delineated. We therefore assessed the hypothesis that sevoflurane pretreatment protected blood-brain-barrier (BBB) via suppression of cell adhesion molecules (CAMs) and matrix metalloproteinases (MMPs) after ischemia. Repeated sevoflurane preconditioning was administered 24 hours before transient middle cerebral artery occlusion (MCAO). Neurologic deficits and expression of CAMs, MMPs and occludin were examined up to 3 days after ischemia. Evans blue (EB) extravasation and electron microscopy was detected at 2 days after ischemia. The data showed that sevoflurane pretreatment markedly improved BBB integrity and neurological outcomes after ischemia, robustly suppressed ischemia-induced decreases of occludin and increases of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), MMP-2, MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1). Sevoflurane pretreatment also suppressed the activation of astrocytes and microglias in ipsilateral cortex and corpus callosum. In conclusion, repeated sevoflurane preconditioning confered potent protection against brain ischemia, partly by improving BBB integrity.