Objective To establish a Wuzhishan minipig model of atherosclerosis (AS) induced by high fat/cholesterol diet, and observe the changes of expression of lipoprotein associated phospholipase A₂ (Lp-PLA₂) in plasma and plaques.Methods 10 Wuzhishan minipigs were randomly divided into 2 groups: The normal control (Ctr, n=4) group was fed with normal diet, and AS model (n=6) group fed with high fat/cholesterol diet for 24 weeks. After the modeling for 24 weeks, the changes of total cholesterol (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C), triglyceride (TG), C-reactive protein (CRP), Lp-PLA₂ activity and composition were detected. The changes of vascular lipid deposition and plaques were assessed by pathology using oil red O staining and HE staining, respectively, and immunohistochemical staining for IL-6 protein expression. Moreover, the expression of Lp-PLA₂ mRNA determined by RT-PCR and protein by Western blot were observed in the abdominal aortic tissues. Results Compared with the control group, the body weight, body mass index (BMI), TC, LDL-C, HDL-C, CRP, Lp-PLA₂ activity and composition and aortic lipid deposition were significantly increased, and AS plaque formation was observed in the AS model group (P < 0.05, P < 0.01). The expression of Lp-PLA₂mRNA and protein and IL-6 protein in abdominal aortic tissues were also significantly increased (P < 0.05). Conclusions Long-term high fat/cholesterol diet feeding for 24 weeks can induce atherosclerosis in Wuzhishan minipigs, and Lp-PLA2 plays a key role in the vascular inflammation and plaque formation.