Lysophosphatidic acid (LPA), a simple lysophospholipid, has potent effects on a variety of cell types. We report here that LPA enhances lipopolysaccharide (LPS)-induced oxidized low density lipoprotein (oxLDL) uptake in mouse primary bone marrow-derived macrophages (BMMs). Our data revealed that both LPA and LPS highly induce the CD14 expression at both messenger RNA and protein levels in BMMs. The role of CD14, one component of the LPS receptor cluster, in LPA-induced biological functions has been unknown. We took several steps to examine the role of CD14 in LPA signaling pathways. Knockdown of CD14 expression nearly completely blocked LPA-, LPS- or LPA plus LPS-induced oxLDL uptake in BMMs, demonstrating for the first time that CD14 is a key mediator responsible for both LPA- and LPS-induced oxLDL uptake/foam cell formation. To determine the molecular mechanism mediating CD14's novel function, we demonstrated that both LPA and LPS significantly induce the scavenger receptor A-1 (SR-AI) expression, and depletion of CD14 levels blocked LPA/LPS-induced SR-AI expression. We further showed that the SR-AI specific antibody, which quenches SR-AI function, blocked LPA and LPS-induced foam cell formation. Thus, SR-AI is the downstream mediator of CD14 in regulating LPA-, LPS-, and LPA/LPS-induced foam cell formation. Taken together, our results provide the first experimental evidence that CD14 is a novel junctional molecule connecting both LPA and LPS pathways and is a key mediator responsible for both LPA- and LPS-induced foam cell formation. The LPA/LPS-CD14-SR-AI nexus might be the new convergent pathway, contributing to the worsening of atherosclerosis.