Formyl peptide receptor-like 1 (FPRL1), which is a G protein-coupled receptor of chemoattractant subfamily, plays an important role in the regulation of host defense against pathogenic infection and the chemotactic and activating effects of Abeta42 on mononuclear phagocytes as well as in the elimination of damaged or pathogen-infected cells. In the present study, we showed that stimulation of FPRL1 agonist ligands (W peptide from a synthetic peptide library, N36 peptide from HIV-1 gp41, and F peptide from HIV-1 envelope protein gp120) elevated endogenous tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in human THP-1 monocytes, primary neutrophils, and mouse leukocytes. Activation of nuclear factor kappaB was required by the FPRL1-mediated TRAIL expression in the human THP-1 cells and primary neutrophils. The increased TRAIL expression in the mice significantly suppressed the growth of transplanted mouse liver tumor cells by inducing apoptotic cell death. Together, these data provide novel evidence for the physiologic role of FPRL1 and TRAIL in tumor immune surveillance and innate immunity, and implicate a novel strategy for cancer therapy by triggering the endogenous TRAIL expression via stimulation of G protein-coupled receptor FPRL1.