Rationale: Histological examination of abdominal aortic aneurysm (AAA) tissues demonstrates extracellular matrix destruction and infiltration of inflammatory cells. Previous work with mouse models of AAA has shown that anti-inflammatory strategies can effectively attenuate aneurysm formation. Thrombospondin-1 is a matricellular protein involved in the maintenance of vascular structure and homeostasis through the regulation of biological functions, such as cell proliferation, apoptosis, and adhesion. Expression levels of thrombospondin-1 correlate with vascular disease conditions. Objective: To use thrombospondin-1–deficient ( Thbs1 ^−/− ) mice to test the hypothesis that thrombospondin-1 contributes to pathogenesis of AAAs. Methods and Results: Mouse experimental AAA was induced through perivascular treatment with calcium phosphate, intraluminal perfusion with porcine elastase, or systemic administration of angiotensin II. Induction of AAA increased thrombospondin-1 expression in aortas of C57BL/6 or apoE−/− mice. Compared with Thbs1 ^+/+ mice, Thbs1 ^−/− mice developed significantly smaller aortic expansion when subjected to AAA inductions, which was associated with diminished infiltration of macrophages. Thbs1 ^−/− monocytic cells had reduced adhesion and migratory capacity in vitro compared with wild-type counterparts. Adoptive transfer of Thbs1 ^+/+ monocytic cells or bone marrow reconstitution rescued aneurysm development in Thbs1 ^−/− mice. Conclusions: Thrombospondin-1 expression plays a significant role in regulation of migration and adhesion of mononuclear cells, contributing to vascular inflammation during AAA development.