The transcription factor NF-κB is activated in neurons and promotes neuronal death in cerebral ischemia. Its target genes include cytosolic phospholipase A-2 (cPLA-2), cyclooxygenase-2 (COX-2), and microsomal prostaglandin E2 synthase-1 (mPGES-1), three genes that are involved in the synthesis of prostaglandin E2 (PGE2). In our study, oxygen glucose deprivation (OGD), an in vitro model of cerebral ischemia, activated NF-κB activity in primary cortical neurons. Furthermore, OGD and the NF-κB activator tumor necrosis factor stimulated the expression of cPLA-2, cyclooxygenase-2 (COX-2), and mPGES-1 and increased the release of PGE2 from neurons. Expression of a constitutively active IκB kinase (IKK) or the NF-κB subunit p65 in neurons stimulated the transcription of cPLA-2, COX-2, and mPGES-1. Finally, inhibition of IKK in neurons blocked the induction of the three genes involved in PGE2 synthesis in vivo. In summary, NF-κB controls the neuronal expression of three genes involved in PGE2 synthesis in cerebral ischemia.