Cathepsin G (CatG) is a serine protease that mediates angiotensin I to angiotensin II (Ang-II) conversion and is highly expressed in human abdominal aortic aneurysms (AAAs). However, it remains untested whether this protease participates in the pathogenesis of AAA. Immunofluorescent double staining demonstrated the expression of CatG in smooth muscle cells (SMCs), macrophages, and endothelial cells in human AAA lesions (n = 12) but not in AAA-free aortas (n = 10). Whereas inflammatory cytokines induced CatG expression, high glucose concentration increased CatG activity in producing Ang-II and angiotensin-converting enzyme in SMCs, which could be fully blocked by a CatG-selective inhibitor or its small interfering RNA. To test whether CatG contributes to AAA development, we generated CatG and low-density lipoprotein receptor double deficient (Ldlr(-/-)Ctsg(-/-)) mice and their littermate controls (Ldlr(-/-)Ctsg(+/+)). Absence of CatG did not affect Ang-II infusion-induced AAAs. In contrast, in Ang-II-independent AAAs induced by periaortic CaCl2 injury (n = 12 per group), CatG deficiency significantly reduced aortic diameter increase (58.33% ± 6.83% vs 31.67% ± 5.75%; P = .007), aortic lesion area (0.35 ± 0.04 mm(2) vs 0.21 ± 0.02 mm(2); P = .005), and aortic wall elastin fragmentation grade (2.75 ± 0.18 vs 1.58 ± 0.17; P = .002) along with reduced lesion collagen content grade (2.80 ± 0.17 vs 2.12 ± 0.17; P = .009) without affecting indices of lesion inflammation, angiogenesis, cell proliferation, or apoptosis. In vitro elastin degradation assays demonstrated that CaCl2-induced AAA lesions from Ldlr(-/-)Ctsg(-/-) mice contained much lower elastinolytic activity than in those from littermate control mice. Gelatin gel zymogram assay suggested that absence of CatG in CaCl2-induced AAA lesions also reduced the activity of elastinolytic matrix metalloproteinases 2 and 9. CatG may contribute to CaCl2-induced experimental AAAs directly through its elastinolytic activity and indirectly by regulating lesion matrix metalloproteinases 2 and 9 activities. Increased expression of CatG in vascular and inflammatory cells of human AAAs and its increased activity in producing Ang-II and angiotensin-converting enzyme by SMCs suggest an additional mechanism by which CatG contributes to AAA lesion progression.