Epidemiologic research has shown a correlation between cigarette smoke and the risk of developing atherosclerosis. The unregulated uptake of modified low density lipoprotein (LDL) is a hallmark of atherosclerotic plaque formation, as it leads to foam cell formation, and may be a key step in the progression of cigarette-smoke-related atherosclerosis. In this study, we examined the mechanistic effects occurring in cigarette-smoke-induced foam cell formation in vitro. Macrophages derived from the human acute monocytic leukemia cell line (THP-1) were treated with mainstream smoke total particulate matter (TPM) from the reference cigarette 3R4F (University of Kentucky) for up to 42h. The cells were subsequently treated for 4 hours with fluorescence-labelled acetylated LDL for quantification of foam cell formation or with acetylated LDL for RNA analysis. The uptake of fluorescence-labelled LDL was enhanced dose-dependently in THP-1 macrophages treated with TPM. Gene expression analysis showed that this effect was not correlated with the expression of scavenger receptors. DNA microarray with pathway analysis revealed the involvement of different pathways. This study showed for the first time that foam cell formation of THP-1 macrophages was accelerated by treatment with TPM, independent of differentially expressed scavenger receptors.