Phagocytosis by macrophages is essential for host defense, i.e. preventing invasion of pathogens and foreign materials. Macrophages engulf immunoglobulin G (IgG)-opsonized particles through the action of the receptors for the Fc of IgG (Fc gamma Rs). Leukotriene B-4 (LTB4) is a classical lipid chemoattractant derived from arachidonic acid. Leukotriene B-4 receptor 1 (BLT1), a high affinity LTB4 receptor, is expressed in a variety of immune cells such as neutrophils, macrophages, and dendritic cells. Although LTB4 has been shown to enhance macrophage phagocytosis, few studies have investigated the intracellular mechanisms involved in this in detail. Furthermore, there have been no reports of the direct cross-talk between LTB4-BLT1 and IgG-Fc gamma Rs signaling. Here, we show that Fc gamma Rs-dependent phagocytosis was attenuated in BLT1-deficient macrophages as compared with wild-type (WT) cells. Moreover, cross-talk between LTB4-BLT1 and IgG-Fc gamma Rs signaling was identified at the level of phosphatidylinositol 3-OH kinase (PI3K) and Rac, downstream of Syk. In addition, the trimeric G(i) protein (G(i)) was found to be essential for BLT1-dependent phagocytosis. Surprisingly, we found that LTB4-BLT1 signaling restores phagocytosis in the absence of Fc gamma Rs signaling. These data indicate that LTB4-BLT1 signaling plays a pivotal role in macrophage phagocytosis and innate immunity.