LPA is a bioactive lysophospholipid ligand present in oxidized low-density lipoprotein. The effects of LPA were investigated, first separately on endothelial cells (EC) and monocytes. Using Ki16425 (a LPA₁ and LPA₃ receptor antagonist), GW9662 (a PPAR antagonist), and pertussis toxin (that inhibits G_i/o ), we demonstrate that LPA enhances IL-8 and MCP-1 expression through a LPA₁ -, LPA₃ -, G_i/o - and PPAR-dependent manner in the EAhy926 cells. The effect of LPA on chemokine overexpression was confirmed in HUVEC cells. LPA was able to enhance monocyte migration at concentrations < 1 µM and to inhibit their migration at LPA concentrations > 1 µM, as demonstrated by using a chemotaxis assay. Then we investigated the effects of LPA on the cross-talk between EC and monocytes by evaluating the chemotactic activity in the supernatants of LPA-treated EC. At 1 µM LPA, both cell types respond cooperatively, favoring monocyte migration. At higher LPA concentration (25 µM), the chemotactic response varies as a function of time. After 4 hours, the chemotactic effect of the cytokines secreted by the EC is counteracted by the direct inhibitory effect of LPA on monocytes. For longer periods of time (24 hours), we observe a monocyte migration, probably due to lowered concentrations of bioactive LPA, given the induction of lipid phosphate phosphatase-2 (LPP-2) in monocytes that may inactivate LPA. These results suggest that LPA activates EC to secrete chemokines that in combination with LPA itself might favor or not interactions between endothelium and circulating monocytes.