C ytosolic phospholipase A_2α (cPLA_2α) hydrolyzes arachidonic acid from cellular membrane phospholipids, thereby providing enzymatic substrates for the synthesis of eicosanoids, such as prostaglandins and leukotrienes. Considerable understanding of cPLA_2α function has been derived from investigations of the enzyme and from cPLA_2α-null mice, but knowledge of discrete roles for this enzyme in humans is limited. We investigated a patient hypothesized to have an inherited prostanoid biosynthesis deficiency due to his multiple, complicated small intestinal ulcers despite no use of cyclooxygenase inhibitors. Levels of thromboxane B₂ and 12-hydroxyeicosatetraenoic acid produced by platelets and leukotriene B₄ released from calcium ionophore–activated blood were markedly reduced, indicating defective enzymatic release of the arachidonic acid substrate for the corresponding cyclooxygenase and lipoxygenases. Platelet aggregation and degranulation induced by adenosine diphosphate or collagen were diminished but were normal in response to arachidonic acid. Two heterozygous single base pair mutations and a known SNP were found in the coding regions of the patient’s cPLA_2α genes (p.[Ser111Pro]+[Arg485His; Lys651Arg]). The total PLA₂ activity in sonicated platelets was diminished, and the urinary metabolites of prostacyclin, prostaglandin E₂, prostaglandin D₂, and thromboxane A₂ were also reduced. These findings characterize what we believe is a novel inherited deficiency of cPLA₂.