ATP-binding cassette transporter A1 (ABCA1), a pivotal regulator of cholesterol efflux from cells to apolipoproteins, plays an important role in cholesterol homeostasis. As an inflammatory factor, IL-1 has been shown to downregulate ABCA1 in macrophages and facilitates foam cell formation. However, the molecular mechanism underlining the downregulated ABCA1 by IL-1 is still elusive. In the present study, we demonstrated that IL-1 downregulated ABCA1 but not ABCG1 at mRNA and protein levels in a time- and dose-dependent manner in THP-1 and A549 cells. IL-1 attenuated ABCA1 promoter activity through an LXR (liver X receptor)-independent pathway, since IL-1 did not alter the expression and activities of LXR/, and deletion of the LXR responsive element from the ABCA1 promoter failed to reverse the IL-1 effect. In contrast, NF-B inhibition by PDTC and MG132 prevented the suppression of ABCA1 by IL-1. Co-transfection with ABCA1 luciferase reporter and the expression plasmids of Rel A decreased ABCA1 promoter activities. An adenovirus expressing IB inhibited NF-B activities and also reversed the IL-1 effect at the promoter activity and protein levels of ABCA1. In addition, IL-1 could induce the production of reactive oxygen species (ROS), and NAC, a scavenger of ROS, reversed the decreased level of ABCA1 induced by IL-1. H₂O₂ decreased ABCA1 at the mRNA and protein levels and the promoter activity. Thus, our data provide strong evidence that ROS and NF-B, but not LXR, mediate the IL-1-induced downregulation of ABCA1 via a novel transcriptional mechanism, which might play an important role of proinflammation in lipid metabolism.