Aim To investigate the mechanism of perilipin 2 (PLIN2) increasing lipid accumulation in macrophages. Methods The experiments were divided into oxidized low density lipoprotein (ox-LDL) group, different PLIN2 expression groups, and different activity Rab18 groups, the levels of Rab18 and acyl-CoA long chain synthetase 3 (ACSL3) protein in high expression and silent expression of PLIN2 macrophages were measured, and the levels of PLIN2, Rab18, and ACSL3 protein expression in high expression PLIN2 macrophages with different activity Rab18 were measured.Western blot was used to detect protein expression levels, immunofluorescence was used to observe the localization of intracellular related proteins, and oil red O staining was used to observe intracellular lipid accumulation. Results The expression levels of Rab18 and ACSL3 in cells with high expression of PLIN2 were increased significantly (P＜0.05), and there was an intracellular phenomenon of co-localization of PLIN2 with Rab18 and ACSL3. The expression level of ACSL3 in high expression macrophages of PLIN2 after transfection with the Rab18 dominant mutant Q67L plasmid (Rab18 activity increased) was increased significantly (P＜0.05), and the number of intracellular lipid droplets was also increased significantly (P＜0.05). Conclusion PLIN2 promotes macrophage lipid accumulation through Rab18 by up-regulating ACSL3.