Macrophage-derived foam cells in atherosclerotic lesions are generally thought to play a major role in the pathology of the disease. Hypoxia-inducible factor-1alpha (HIF-1alpha) was recently found to play an important role in atherosclerosis. Here we applied RNA interference to study the role of HIF-1alpha in foam cell formation in vitro. Transfection of HIF-1alpha-siRNA reduced HIF-1alpha synthesis as measured on mRNA and protein level by real-time RT-PCR, Western blot. It was found that RNA interference for HIF-1alpha with small interfering RNAs (HIF-1alpha-siRNA) inhibits foam cell formation by the human monoblastic cell line (U937) which was treated with oxidized low-density lipoprotein (ox-LDL) while the majority of atherosclerosis-related genes, such as cyclooxygenase-2 (COX-2), vascular cell adhesion molecule-1 (VCAM-1), interleukin-1beta (IL-1beta), and so on, were down-regulated, through large scale gene expression analysis using DNA microarrays. These data demonstrate that induction of HIF-1alpha by atherogenic factors may be a key step in coordinating the cellular events that result in atherosclerotic lesions.