Granulocyte-colony stimulating factor (G-CSF) is reported to be neuroprotective after transient cerebral ischemia with respect to decreasing lesion volume and enhancing functional recovery. We investigated whether G-CSF is neuroprotective after permanent ischemia and the possible mechanisms underlying this neuroprotection. Mice underwent permanent or 60-minute middle cerebral artery occlusion (MCAO) and received G-CSF (50 microg/kg) or vehicle at the onset or 1 hour post-MCAO. Forty-eight hours after transient MCAO, structural magnetic resonance imaging revealed a significant reduction (50%) in the amount of edematous tissue present in G-CSF-treated mice (p < 0.05). G-CSF treatment also prevented a significant increase in ipsilateral brain water content that was present in vehicle-treated mice after transient (p < 0.05) and permanent (p < 0.001) MCAO. Forty-eight hours after permanent MCAO, G-CSF decreased (50%) the cortical lesion volume (p < 0.05). Using real-time polymerase chain reaction, we found that G-CSF treatment significantly suppressed (p < 0.05) the injury-induced upregulation of IL-1beta mRNA while having no effect on TNFalpha and NOS-2 mRNA expression. This suggests that part of the neuroprotection may be attributed to the ability of G-CSF to reduce the inflammatory response.