Cardiovascular diseases due to atherosclerosis are the leading cause of death worldwide. In recent years, novel therapeutics designed to enhance high-density lipoprotein (HDL) activity as a treatment for atherosclerosis have been explored. Of particular interest is the use of amphipathic α-helical peptides to mimic the action of the main HDL protein, apolipoprotein (Apo)AI. Immunomodulatory peptides share many physical and functional properties with ApoAI and its mimetics; we therefore hypothesized that they too might be capable of enhancing cholesterol efflux. The aim of this study was to determine whether a potent immunomodulatory peptide, innate defence regulator (IDR)-1018, could promote cholesterol efflux from cells. Here, we report that IDR-1018 induced a dose-dependent increase in ApoAI on the cell surface and ATP-binding cassette transporter A1 (ABCA1) protein levels. Functional assays revealed that low doses of IDR-1018 improved HDL-mediated suppression of intracellular cholesteryl ester accumulation in macrophages and enhanced HDL-mediated cellular cholesterol efflux from smooth muscle cells and macrophages. Based on these results we propose that natural and synthetic immunomodulatory peptides like IDR-1018 represent a large new group of peptides that could be developed for the treatment of atherosclerosis.