CD43 is a glycosylated surface protein abundantly expressed on lymphocytes. Its role in immune responses has been difficult to clearly establish, with evidence supporting both costimulatory and inhibitory functions. In addition, its contribution to disease pathogenesis remains elusive. Using a well-characterized murine model of elastase-induced abdominal aortic aneurysm (AAA) that recapitulates many key features of the human disease, we established that the presence of CD43 on T cells is required for AAA formation. Moreover, we found that IFN-γ-producing CD8+ T cells, but not CD4 + T cells, promote the development of aneurysm by enhancing cellular apoptosis and matrix metalloprotease activity. Reconstitution with IFN-γ-producing CD8+ T cells or recombinant IFN-γ promotes the aneurysm phenotype in CD432/2 mice, whereas IFN-γ antagonism abrogates disease in wildtype animals. Furthermore, we showed that the presence of CD43 with an intact cytoplasmic domain capable of binding to ezrinradixin- moesin cytoskeletal proteins is essential for optimal in vivo IFN-γ production by T cells and aneurysm formation.We have thus identified a robust physiologic role for CD43 in a relevant animal model and established an important in vivo function for CD43-dependent regulation of IFN-γ production. These results further suggest that IFN-γ antagonism or selective blockade of CD43+CD8+ T cell activities merits further investigation for immunotherapy in AAA.