Few reported inhibitors of secretory phospholipase A2enzymes truly inhibit the IIa human isoform (hnpsPLA2-IIa) noncovalently at submicromolar concentrations. Herein, the simple chiral precursor D-tyrosine was derivatised to give a series of potent new inhibitors of hnpsPLA2-IIa. A 2.2-Å crystal structure shows an inhibitor bound in the active site of the enzyme, chelated to a Ca2+ion through carboxylate and amide oxygen atoms, H-bonded through an amide NH group to His48, with multiple hydrophobic contacts and a T-shaped aromatic-group–His6 interaction. Antiinflammatory activity is also demonstrated for two compounds administered orally to rats.