The transcription factor NF-kappa B is a regulator of cell death or survival. To investigate the role of NF-kappa B in neuronal cell death, we studied its activation in a rodent model of stroke. In the ischemic hemisphere, NF-kappa B was activated, as determined by increased expression of an NF-kappa B-driven reporter transgene, nuclear translocation of NF-kappa B in neurons and enhanced DNA binding of NF-kappa B subunits RelA and p50. In p50 knockout mice, ischemic damage was significantly reduced. This indicates a cell death-promoting role of NF-kappa B in focal ischemia. NF-kappa B may provide a new pharmacological target in neurologic disease.