Triggering receptor expressed on myeloid cells 1 (TREM-1) is an activating receptor expressed on neutrophils and monocytes that amplifies inflammation induced by stimulation of pattern-recognition receptors. In this study, several lines of evidence are presented that TREM-1 interacts with the toll-like receptor 4 (TLR4) receptor complex, or is a component of this complex. Blocking anti-TREM-1 antibodies specifically inhibited LPS-induced TNF-α production, while the alternative approach of blocking TLR4 by a specific inhibitor led to a down-regulation of the effects of TREM-1 cross-linking. These data are in line with the TLR4-TREM1 co-localization in human neutrophils and suggests that, at least some of the biological effects of TREM-1 may be due to its interaction with the TLR4/LPS-receptor complex.