ATP-binding cassette transporter A1 (ABCA1) plays a central role in promoting cholesterol efflux from macrophages, thereby reducing the risk of foam cell formation and atherosclerosis. The expression of ABCA1 is induced by members of the nuclear receptor family of transcription factors, including retinoic acid receptors (RARs). A key innate immunity signaling kinase, IRAK-1, has been associated with an increased risk of atherosclerosis in humans and mice. This prompted us to investigate the potential connection between IRAK-1 and the expression of ABCA1. Here, we demonstrate that nuclear RARα levels are dramatically elevated in IRAK-1^−/− macrophages. Correspondingly, IRAK-1^−/− macrophages exhibit increased expression of ABCA1 mRNA and protein, as well as elevated cholesterol efflux in response to the RAR ligand ATRA. Analysis of the ABCA1 proximal promoter revealed binding sites for both RAR and NFAT. Chromatin immunoprecipitation assays demonstrated increased binding of RARα and NFATc2 to the ABCA1 promoter in IRAK-1^−/− macrophages compared to wild-type macrophages. Additionally, lipopolysaccharide pretreatment reduced the nuclear levels of RARα and decreased ABCA1 expression and cholesterol efflux in wild-type but not in IRAK-1^−/− cells. In summary, this study reveals a novel connection between innate immunity signaling processes and the regulation of ABCA1 expression in macrophages and defines a potential therapeutic target for treating atherosclerosis.