The transcription factor NFκB is activated by various signals associated with brain injury, including tumor necrosis factor (TNF), oxidative insults, and amyloid β-peptide (Aβ). We recently reported that TNFs activate NFκB in neurons and protect them against excitotoxic and oxidative insults, including Aβ toxicity. We now report that C2-ceramide (C2), a membrane-permeant activator of NFκB, protects cultured rat hippocampal neurons against death induced by glutamate, FeSO4, and Aβ. Protection was concentration dependent, specific (a ceramide analogue known not to activate NFκB was ineffective), required pretreatment, and was blocked by inhibitors of RNA and protein synthesis. Lipid peroxidation and accumulation of cellular peroxides induced by glutamate, FeSO4, and Aβ were significantly attenuated in neurons pretreated with C2. The data indicate that C2 induces antioxidant pathways in neurons and suggest novel approaches for reducing neuronal injury in both acute and chronic neurodegenerative conditions.