Induction of an inflammatory monocyte phenotype by activated platelets is implicated in the pathogenesis of inflammatory diseases, including atherosclerosis. In this study, we investigated the early signaling events associated with this platelet-induced inflammatory phenotype. We report that coculture of human monocytes with activated platelets induces phosphorylation of Akt, together with rapid mobilization of intracellular Ca(2+), and show that these signaling events can be uncoupled from monocyte binding to activated platelets. Specifically, Ab-inhibition studies and incubation of monocytes with activated platelet supernatant highlighted a role for secreted product(s) of activated platelets. We also identified a role for pertussis toxin-sensitive G protein-coupled receptors and excluded key candidates platelet-activating factor receptor and CCR5. Our results suggest that inhibition of monocyte-platelet interactions via PSGL-1 or P-selectin is not sufficient to prevent platelet-mediated monocyte activation in an inflammatory context. These findings have important implications for the development of therapeutics to treat diseases in which platelet-monocyte complexes are implicated in pathogenesis.