Aim To explore the effect and significance of fatty acid binding protein 4 (FABP4) on the formation of foam cells and the accumulation of cholesterol induced by homocysteine. Methods The macrophage-derived foam cell model of THP-1 monocytic cell line was duplicated and oil red O staining was used to validate whether the model was successfully established in vitro, and foam cells were treated with 100 μmol/L homocysteine. The protein and mRNA expressions of FABP4 in the foam cells were detected by Western blot and real time-polymerase chain reaction (RT-PCR).The FABP4 recombinant plasmid was constructed and then transfected to foam cells which had been identified by restriction enzyme digestion and fluorescent microscope respectively. Results Cytoplasm was filled with large quantities of red lipid droplets and the nuclear was stained to blue, and the content of total cholesterol treated with 100 μmol/L Hcy were significantly increased to 2.4-fold. The results of RT-PCR and Western blot exposed an up-expressed FABP4 mRNA and protein in 100 μmol/L Hcy group (P＜0.01). GFP protein expressed at a high level after the FABP4 recombinant plasmid was transfected into foam cells and the expression of FABP4 was also greatly elevated, the content of TC was significantly increased to 1.9-fold, and the difference was significant compared to the control group (P＜0.05 or P＜0.01). Conclusion The up-regulation of FABP4 might be one of the important mechanisms for Hcy which mediated the accumulation of cholesterol in foam cells.