Macrophages are called upon to ingest both IgG-coated targets and apoptotic cells. Important roles for tyrosine kinase Syk and leukotriene B4 (LTB4) are recognized in FcgammaR-mediated phagocytosis. Here we evaluated the roles of Syk and LTB4 in macrophage phagocytosis of apoptotic thymocytes versus IgG-coated erythrocytes. Macrophage ingestion of apoptotic thymocytes was not influenced by exogenous or endogenous LTB4 nor associated with Syk activation (phosphorylation). By contrast, LTB4 dose-dependently amplified FcgammaR-mediated phagocytosis as well as Syk activation. Furthermore, a role for endogenous LTB4 in Syk activation during FcgammaR-mediated phagocytosis was demonstrated using pharmacologic and genetic abrogation of 5-lipoxygenase. LTB4 was unique among 5-lipoxygenase products in this regard, since LTD4 and 5-hydroxyeicosatetraenoic acid (HETE) were unable to amplify Syk activation in response to FcgammaR engagement. Ca2+ chelation studies revealed that FcgammaR-mediated Syk activation as well as LTB4 amplification thereof was Ca2+ regulated. These 2 parallel phagocytic processes therefore exhibit initial divergence in signal transduction events, with Syk activation being an LTB4-regulated event in FcgammaR-mediated but not apoptotic cell ingestion. As LTB4 is an important proinflammatory product of macrophages, we speculate that this divergence evolved to permit FcgammaR-mediated phagocytosis to proceed in an inflammatory milieu, while apoptotic cell clearance is noninflammatory.