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Secreted phospholipase A2 group X (sPLA₂-X) is one of the most potent enzymes of the phospholipase A₂ lipolytic enzyme superfamily. Its high catalytic activity toward phosphatidylcholine (PC), the major phospholipid of cell membranes and low-density lipoproteins (LDL), has implicated sPLA₂-X in chronic inflammatory conditions such as atherogenesis. We studied the role of sPLA₂-X enzyme activity in vitro and in vivo, by generating sPLA₂-X-overexpressing macrophages and transgenic macrophage-specific sPLA₂-X mice. Our results show that sPLA₂-X expression inhibits macrophage activation and inflammatory responses upon stimulation, characterized by reduced cell adhesion and nitric oxide production, a decrease in tumor necrosis factor (TNF), and an increase in interleukin (IL)-10. These effects were mediated by an increase in IL-6, and enhanced production of prostaglandin E₂ (PGE₂) and 15-deoxy …