Lipoxins (LX) are lipoxygenase-derived eicosanoids generated during inflammation. LX inhibit polymorphonuclear neutrophil (PMN) chemotaxis and adhesion and are putative braking signals for PMN-mediated tissue injury. In this study, we report that LXA 4 promotes another important step in the resolution phase of inflammation, namely, phagocytosis of apoptotic PMN by monocyte-derived macrophages (Mφ). LXA 4 triggered rapid, concentration-dependent uptake of apoptotic PMN. This bioactivity was shared by stable synthetic LXA 4 analogues (picomolar concentrations) but not by other eicosanoids tested. LXA 4-triggered phagocytosis did not provoke IL-8 or monocyte chemoattractant protein-1 release. LXA 4-induced phagocytosis was attenuated by anti-CD36, α v β 3, and CD18 mAbs. LXA 4-triggered PMN uptake was inhibited by pertussis toxin and by 8-bromo-cAMP and was mimicked by Rp-cAMP, a protein kinase A inhibitor. LXA 4 attenuated PGE 2-stimulated protein kinase A activation in Mφ. These results suggest that LXA 4 is an endogenous stimulus for PMN clearance during inflammation and provide a novel rationale for using stable synthetic analogues as anti-inflammatory compounds in vivo.