BACKGROUND The aim of this study was to explore the role of intermedin and its mechanism in cholesterol efflux of macrophage THP-1 and RAW264.7 cell lines in atherosclerosis (AS). MATERIAL AND METHODS ApoE-/- mice were fed with a high-fat diet, and the concentrations of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured. The lipidoses of the aortic sinus were analyzed by hematoxylin and eosin staining, and the cAMP level was detected by enzyme-linked immunosorbent assay (ELISA). The expressions of ATP-binding cassette transporter (ABCA1) were tested by real-time PCR and Western blot analysis. RESULTS IMD decreased serum TC and LDL-C, and increased serum HDL-C level in apoE-/- mice and attenuated AS plaque areas. In vitro, IMD increased intracellular cAMP concentration in a dose-dependent manner in THP-1 and RAW264.7 cell lines, which enhanced the expression of ABCA1 and increased cholesterol efflux rate. However, this effect was inhibited by PKAI in the RAW 264.7 cell line but not in the THP-1 cell line. CONCLUSIONS IMD can ameliorate the development of AS in ApoE-/- mice and regulate cholesterol balance in the RAW264.7 cell line through the cAMP-PKA pathway.