<p>Atherosclerotic lesions comprise different populations of macrophages, including lipid-laden macrophage foam cells and non-foamy, inflammatory macrophages, which play distinct roles in disease progression. Non-foamy macrophages express higher levels of inflammarafts – enlarged, cholesterol-rich lipid rafts hosting assemblies of inflammatory receptors – compared to foam cells in atherosclerotic lesions of <i>Ldlr</i>^{<i>−/−</i>} mice. Apolipoprotein A-I binding protein (AIBP) has been shown to control lipid raft dynamics. This study investigated the effect of systemic AIBP deficiency on inflammaraft expression in foam cells and non-foamy macrophages in atherosclerotic lesions of hypercholesterolemic mice. A larger number of foam cells, with increased neutral lipid accumulation, populated atherosclerotic lesions in <i>Apoa1bp</i>^{<i>−/−</i>}<i>Ldlr</i>^{<i>−/−</i>} mice compared to <i>Ldlr</i>^{<i>−/−</i>} mice. Importantly, AIBP-deficient foam cells expressed higher levels of TLR4 dimers and lipid rafts (markers of inflammarafts) than control mice, accompanied by larger atherosclerotic lesions and larger necrotic cores compared to <i>Ldlr</i>^{<i>−/−</i>} mice. In a model of foam cells, <i>Apoa1bp</i>^{<i>−/−</i>} bone marrow-derived macrophages incubated with oxidized LDL had increased expression of inflammation and atherosclerosis related genes. These results indicate that AIBP deficiency results in a phenotype shift in foam cells, characterized by increased lipid accumulation and increased expression of inflammarafts, and it correlates with the development of advanced atherosclerotic plaques.</p>