Heterozygous loss-of-function SMAD3 (Mothers against decapentaplegic homolog 3) mutations lead to aneurysm-osteoarthritis syndrome (AOS). In the present study, we found that mice lacking Smad3 had a vascular phenotype similar to AOS, marked by the progressive development of aneurysms. These aneurysms were associated with various pathological changes in transmural inflammatory cell infiltration. Bone marrow transplants from Smad3^–/– mice induced aortitis and aortic root dilation in irradiated WT recipient mice. Transplantation of CD4⁺ T cells from Smad3^–/– mice also induced aortitis in Smad3^+/+ recipient mice, while depletion of CD4⁺ T cells in Smad3^–/– mice reduced the infiltration of inflammatory cells in the aortic root. Furthermore, IFN-γ deficiency increased, while IL-17 deficiency decreased, disease severity in Smad3^+/– mice. Cytokine secretion was measured using a cytokine quantibody array, and Smad3^–/– CD4⁺ T cells secreted more GM-CSF than Smad3^+/+ CD4⁺ T cells. GM-CSF induced CD11b⁺Gr-1⁺Ly-6C^hi inflammatory monocyte accumulation in the aortic root, but administration of anti–GM-CSF mAb to Smad3^–/– mice resulted in significantly less inflammation and dilation in the aortic root. We also identified a missense mutation (c.985A>G) in a family of thoracic aortic aneurysms. Intense inflammatory infiltration and GM-CSF expression was observed in aortas specimens of these patients, suggesting that GM-CSF is potentially involved in the development of AOS.