FGF21, a member of the fibroblast growth factor superfamily, is an important endogenous regulator of systemic glucose and lipid metabolism. Elevated serum FGF21 levels have been reported in subjects with coronary heart disease and carotid artery plaques. However, whether FGF21 is associated with atherosclerotic diseases remains unclear. In this study, the effects of FGF21 on cholesterol efflux in THP1 macrophage-derived foam cells and the underlying mechanisms were investigated. THP1 macrophage-derived foam cells were incubated with 0, 25, 50, 100, 200, and 400 ng/mL of FGF21 for varying time periods (0, 6, 12, and 24 h). Cholesterol efflux onto apoA-1 was assessed by high-performance liquid chromatography assays, while change in ABCA1 expression was analyzed by western blot and real-time quantitative PCR. Incubation was performed with the ERK1/2-specific inhibitor PD98059, PPARγ-specific inhibitor GW9662, and LXRα siRNA. Our results show that FGF21 promotes cholesterol efflux and ABCA1 expression in THP1 macrophage-derived foam cells in a dose- and time-dependent manner. In addition, inhibition of ERK1/2 or PPARγ, or knockdown of LXRα attenuated FGF21-mediated promotion of ABCA1 expression and cholesterol efflux. These results demonstrate that FGF21 can promote cholesterol efflux by upregulating ABCA1 through the ERK1/2-PPARγ-LXRα pathway in THP1 macrophage-derived foam cells.