Aim To investigate effect of OX40-OX40L signal on the expression of cyclophilin A （CyPA） in atherosclerotic plaque of apolipoprotein E gene knockout （ApoE^－/－） mice. Methods Atherosclerotic plaque model was produced by perivascular carotid collar placement in ApoE^－/－ mice. 48 male ApoE^－/－ mice were anesthetized by intraperitoneal injection of ketamine. Subsequently, the right common carotid artery was separated, and Silicone Collar was placed on the right common carotid artery. ApoE^-/- mice were randomly allocated to inhibition group （intraperitoneal injection of anti-OX40L 200 μg, once a week, 6 weeks）, stimulation group （intraperitoneal injection of anti-OX40 200 μg, once a week, 6 weeks） and control group （intraperitoneal injection of IgG2b 200 μg, once a week, 6 weeks）, mice were sacrificed after high fat diet and intraperitoneal injection of antibodies was received for 6 weeks. The expression of CyPA protein and mRNA levels in atherosclerotic plaque were detected by immunohistochemisty, Western blot, qRT-PCR, respectively. Results Dealing with perivascular carotid collar placement and high fat diet in ApoE^－/－ mice after 6 weeks, plaque formation, part of intima and media thickening and elastic lamina deformation were detected in control. Compared with control group, the carotid sections of plaque area of stimulation group were significantly increased, while those in inhibition group were significantly decreased, the expressions of CyPA protein and mRNA were significantly increased in atherosclerotic plaque （P<0.05）. However, after intraperitoneal injection of anti-OX40L to inhibit OX40-OX40L ligand, the expressions of CyPA protein and mRNA were significantly decreased in atherosclerotic plaque （P<0.05）. Conclusion The expression of CyPA in ApoE^－/－ mice is modulated by the OX40-OX40L signal.