Phospholipase A(2) (PLA(2)) enzymes are critical regulators of prostaglandin and leukotriene synthesis and can directly modify the composition of cellular membranes(1,2). PLA(2) enzymes release fatty acids and lysophospholipids, including the precursor of platelet-activating factor, PAF, from phospholipids. Free fatty acids, eicosanoids, lysophospholipids and PAF are potent regulators of inflammation(1,3,4), reproduction(5-7) and neurotoxicity(1,8,9). The physiological roles of the various forms of PLA(2) are not well defined. The cytosolic form, cPLA(2), preferentially releases arachidonic acid from phospholipids and is regulated by changes in intracellular calcium concentration(10,11). We have now created ’knockout’ (cPLA(2)(-/-)) mice that lack this enzyme, in order to evaluate its physiological importance. We find that cPLA(2)(-/-) mice develop normally, but that the females produce only small litters in which the pups are usually dead, Stimulated peritoneal macrophages from cPLA(2)(-/-) animals did not produce prostaglandin E-2 or leukotriene B-4 or C-4. After transient middle cerebral artery occlusion, cPLA(2)(-/-) mice had smaller infarcts and developed less brain oedema and fewer neurological deficits. Thus cPLA(2) is important for macrophage production of inflammatory mediators, fertility, and in the pathophysiology of neuronal death after transient focal cerebral ischaemia.