Aberrant activation of macrophages in arterial walls by oxidized lipoproteins can lead to atherosclerosis. Oxidized lipoproteins convert macrophages to foam cells through lipid uptake and TLR signaling. To investigate the relative contributions of lipid uptake and TLR signaling in foam cell formation, we established an in vitro assay using liposomes of defined lipid compositions. We found that TLRs signaling through Toll/IL-1R domain-containing adapter inducing IFN-β promoted foam cell formation by inducing both NF-κB signaling and type I IFN production, whereas TLRs that do not induce IFN, like TLR2, did not enhance foam cell formation. Addition of IFN-α to TLR2 activator promoted robust foam cell formation. TLR signaling further required peroxisome proliferator-activated receptor α, as inhibition of peroxisome proliferator-activated receptor α blocked foam cell formation. We then investigated the ability of endogenous microparticles (MP) to contribute to foam cell formation. We found that lipidcontaining MP promoted foam cell formation, which was enhanced by TLR stimulation or IFN-α. These MP also stimulated foam cell formation in a human skin model. However, these MP suppressed TNF-α production and T cell activation, showing that foam cell formation can occur by immunosuppressive MP. Taken together, the data reveal novel signaling requirements for foam cell formation and suggest that uptake of distinct types of MP in the context of activation of multiple distinct TLR can induce foam cell formation.