OBJECTIVES We try to clear the relationship between high-sensitive C-reactive protein (hsCRP) release and abdominal aortic aneurysm formation. METHODS AND RESULTS A rabbit abdominal aortic aneurysm model was created by elastase perfusion. At days 10, 20, and 30 after elastase perfusion, mean serum hsCRP levels detected by ELISA increased over 200% over their basal level (n = 11, P < 0.05). Serum hsCRP levels were significantly higher in the aneurysm groups than in the sham controls by day 5 (n = 11, P < 0.05) and were positively correlated with percentage vessel diameter changes in the aneurysm group by day 10 (r = 0.8012, n = 33, P < 0.05). In the aneurysm group, increased serum CRP was derived from the liver in early stages, yet from dilated vessels in the later stages, as shown by immunostaining, western blot, and reverse transcriptase-PCR. Similar increased hsCRP levels were also observed in dissected rabbit aortic ring explants from the aneurysm model. Pretreatment with the stretch-activated channel blockers gadolinium or streptomycin, as well as nuclear factor-kappaB inhibitor SN50, blocked hsCRP production in the dilated aortic rings. Stretch-activated channel blockers also inhibited the activation of nuclear factor-kappaB. CONCLUSION During abdominal aortic aneurysm formation, increased serum hsCRP levels derive from aneurysmal arteries with degenerating elastic lamina. This process is mediated by mechanical stretch-activated channel-dependent nuclear factor-kappaB translocation to the nucleus.