Kallistatin (KS), encoded by SERPINA4, was suggested to play a protective role in many cardiovascular diseases. However, its role in the pathogenesis of abdominal aortic aneurysm (AAA) remains unclear. The aim of this study was to examine the potential association of KS with AAA pathogenesis. We examined KS (SERPINA4) expression in human AAA by PCR, immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay (ELISA) and analyzed correlations between kallistain and clinical data. We then analyzed the effect of recombinant KS on AAA formation and the Wingless (Wnt) signaling pathway in a mouse AAA model developed by angiotensin II (AngII) infusion to apolipoprotein E-deficient (ApoE-/-) mice. In AAA tissue samples, KS was significantly increased compared with samples from the control group (P<0.001, P<0.001, respectively). Clinically, decreased SERPINA4 expression in AAA tissue samples represented an increased rate of iliac artery aneurysm [odds ratio (OR): 0.017; P=0.040]. And decreased plasma KS level represented a high risk for rupture (OR: 0.837; P=0.034). KS inhibited AAA formation and blocked the Wnt signaling pathway in AngII-infused ApoE-/- mice. The present study demonstrates that aberrant changes in KS expression occur in AAA. KS plays an important anti-inflammatory role and showed important clinical correlations in AAA. Decreased KS (SERPINA4) level is a risk factor of AAA rupture. Our pre-clinical animal experiments indicate that treatment with recombination KS suppresses AngII-induced aortic aneurysm formation and might be a new target for the drug therapy of AAA. 2020 Cardiovascular Diagnosis and Therapy. All rights reserved.