Bioactive lipids such as the prostaglandins have been reported to have various cytoprotective or toxic properties in acute and chronic neurological conditions. The roles of PGF(2α) and its receptor (FP) are not clear in the pathogenesis of ischemic brain injury. Considering that this G-protein coupled receptor has been linked to intracellular calcium regulation, we hypothesized that its blockade would be protective. We used FP antagonist (AL-8810) and FP receptor knockout (FP(-/-)) mice in in vivo and in vitro stroke models. Mice that were treated with AL-8810 had 35.7±6.3% less neurologic dysfunction and 36.4±6.0% smaller infarct volumes than did vehicle-treated mice after 48h of permanent middle cerebral artery occlusion (pMCAO); FP(-/-) mice also had improved outcomes after pMCAO. Blockade of the FP receptor also protected against oxygen-glucose deprivation (OGD)-induced cell death and reactive oxygen species formation in slice cultures. Finally, we found that an FP receptor agonist dose dependently increased intracellular Ca(2+) levels in cultured neurons and established that FP-related Ca(2+) signaling is related to ryanodine receptor signaling. These results indicate that the FP receptor is involved in cerebral ischemia-induced damage and could promote development of drugs for treatment of stroke and acute neurodegenerative disorders.