Aim To investigate the mechanism of fibroblast growth factor 21 (FGF21) in promoting cholesterol efflux from foam cells. Methods THP-1 derived foam cells were treated with FGF21 at different concentrations (0,0, 0,0, 400 μg/L) for 24 hours and 200 μg/L FGF21 at different time (0,6, 2,4, 48 h), Western blot, laser confocal were used to detect LC3, and MDC staining for autophagosomes analysis, HPLC, oil red O staining for intracellular cholesterol accumulation measurement, and liquid scintillation counting for cholesterol efflux detection. Results After 200 μg/L, 400 μg/L FGF21 and 200 μg/L FGF21 were applied for 24 h and 48 h, the levels of total cholesterol (TC), free cholesterol (FC) and cholesterol ester (CE) in foam cells were significantly reduced, while their cholesterol efflux was significantly enhanced. Mechanism studies found that FGF21 induced the formation of autophagosomes in foam cells, and the conversion rate of microtubule-associated protein Ⅰ light chain3 (LC3-Ⅰ) to microtubule-associated protein Ⅱ light chain3 (LC3-Ⅱ) was significantly increased. However, after autophagy was inhibited with autophagy-related gene 5(ATG5) siRNA or 3-methyladenine (3-MA) or Bafilomyein A1 (BafA1), effect of FGF21 on decreasing TC, FC, CE and lipid accumulation, and increasing cholesterol efflux were reduced. Conclusion FGF21 promotes cholesterol efflux in foam cells by up-regulating autophagy.