This chapter explores the divergent pathways of inflammatory infiltration of the mural layers of blood vessels in large and medium vessel vasculitis and contrasts these patterns to the pattern observed in atherosclerosis. Also highlighted is the immune-mediated inflammation that occurs in connective tissue disease and its impact on lipid-driven vascular injury. The progression of inflammation and recruitment of immunomodulators in large/medium vessel vasculitis occurs from the “outside in” starting in the vasa vasorum and moving inward as compared to atherosclerosis where monocyte damage starts in the intimal layer and moves outward. This chapter also delves into the higher burden of atherosclerosis in connective tissue disease patient populations, as seen in persons diagnosed with systemic lupus erythematosus and rheumatoid arthritis. The exploration of these disparate mechanisms of vessel wall damage may be helpful in guiding the development of novel therapies and preventative measures with the goal of attenuating the augmented cardiovascular risk that accompanies long-term autoimmune inflammation.