Expression of group IIA secretory phospholipase A 2 (sPLA 2 -IIA) is documented in the cerebral cortex (CTX) after ischemia, suggesting that sPLA 2 -IIA is associated with neurodegeneration. However, how sPLA 2 -IIA is involved in the neurodegeneration remains obscure. To clarify the pathologic role of sPLA 2 -IIA, we examined its neurotoxicity in rats that had the middle cerebral artery occluded and in primary cultures of cortical neurons. After occlusion, sPLA 2 activity was increased in the CTX. An sPLA 2 inhibitor, indoxam, significantly ameliorated not only the elevated activity of the sPLA 2 but also the neurodegeneration in the CTX. The neuroprotective effect of indoxam was observed even when it was administered after occlusion. In primary cultures, sPLA 2 -IIA caused marked neuronal cell death. Morphologic and ultrastructural characteristics of neuronal cell death by sPLA 2 -IIA were apoptotic, as evidenced by condensed chromatin and fragmented DNA. Before apoptosis, sPLA 2 -IIA liberated arachidonic acid (AA) and generated prostaglandin D 2 (PGD 2 ), an AA metabolite, from neurons. Indoxam significantly suppressed not only AA release, but also PGD 2 generation. Indoxam prevented neurons from sPLA 2 -IIA-induced neuronal cell death. The neuroprotective effect of indoxam was observed even when it was administered after sPLA 2 -IIA treatment. Furthermore, a cyclooxygenase-2 inhibitor significantly prevented neurons from sPLA 2 -IIA-induced PGD 2 generation and neuronal cell death. In conclusion, sPLA 2 -IIA induces neuronal cell death via apoptosis, which might be associated with AA metabolites, especially PGD 2 . Furthermore, sPLA 2 contributes to neurodegeneration in the ischemic brain, highlighting the therapeutic potential of sPLA 2 -IIA inhibitors for stroke.