Abstract: Ceramide is a pro‐apoptotic lipid messenger that induces oxidative stress and may mediate apoptosis in cerebral endothelial cells (CECs) induced by TNF‐α/cycloheximide, lipopolysaccharide, oxidized LDL, IL‐1, and amyloid peptide. Exposure of CECs to C₂ ceramide for 12 h caused cell death in a concentration‐dependent manner, with a LC₅₀ of 30 μM. Statins are inhibitors of 3‐hydroxyl‐3‐methyl coenzyme A reductase which is the rate‐limiting enzyme for cholesterol biosynthesis. Pretreatment with pravastatin at 20 μM for 16 h substantially attenuated ceramide cytotoxicity in mouse CECs. Increases in vascular endothelial growth factor (VEGF) expression were detected within 1‐3 h after pravastatin treatment. This pravastatin action was accompanied by the activation of hypoxia‐inducible factor‐1 (HIF‐1), a transcription factor known to activate VEGF expression. These results raise the possibility that pravastatin may protect CECs against ceramide‐induced death via the HIF‐VEGF cascade.