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We examined brain phospholipid metabolism in mice in which the cytosolic phospholipase A2 (cPLA2, Type IV, 85 k11111111111111111135) was knocked out (cPLA2−/− mice). Compared with controls, these mice demonstrated altered brain concentrations of several phospholipids, reduced esterified linoleate, arachidonate, and docosahexaenoate in choline glycerophospholipid, and reduced esterified arachidonate in phosphatidylinositol. Unanesthetized cPLA2−/− mice had reduced rates of incorporation of unlabeled arachidonate from plasma and from the brain arachidonoyl-CoA pool into ethanolamine glycerophospholipid and choline glycerophospholipid, but elevated rates into phosphatidylinositol. These differences corresponded to altered turnover and metabolic loss of esterified brain arachidonate. These results suggests that cPLA2 is necessary to maintain normal brain concentrations of phospholipids and of their esterified polyunsaturated fatty acids.Reduced esterified arachidonate and docosahexaenoate may account for the resistance of the cPLA2−/− mouse to middle cerebral artery occlusion, and should influence membrane fluidity, neuroinflammation, signal transduction, and other brain processes.