In this study, we demonstrated that CD137-CD137L interaction contributes to the development of atherosclerosis; CyPA is significantly suppressed by the inhibition of CD137-CD137L and is stimulated by the activation of CD137-CD137L signaling pathway in ApoE−/− mice; CyPA inhibition impairs the proatherogenic role of anti-CD137; and ectopic expression of CyPA diminishes the atherosclerotic suppressor function of anti-CD137L, indicating that the effect of CD137-CD137L on atherosclerosis is at least partially mediated by regulation of CyPA. Here, APOE is linked to atherosclerosis.