Open aortic surgery evokes a systemic inflammatory response and is associated with high morbidity and mortality. Purinergic signaling has been shown to be crucial for maintaining vascular integrity and attenuating inflammation related to hypoxia. The involvement of purinergic signaling in cross clamping of major human arteries is unknown. Our aim was to compare systemic inflammatory responses and hypoxia-induced purinergic signaling in patients undergoing either open infra-renal abdominal aortic repair or infra-inguinal revascularization. Pre- and 24 h postoperative blood samples were gathered from 6 patients undergoing aortic clamping and 6 similar patients undergoing common femoral artery cross-clamping. Using Biorad Multipex (TM) T 21- and 27-panels 48 different cytokines, chemokines and growth factors were analyzed, in addition to circulating levels of ATP, ADP, CD39, CD73 and HIF-1 alpha, and compared between the groups. Several inflammatory cytokines were elevated from baseline levels after aortic clamping, but not after femoral cross clamping. Most pronoun rises were seen in IL-6 (667 %, P = 0.016) and HGF (760 %, P = 0.016). HIF-1 alpha values showed a steady increase after clamping of either artery unless the subject underwent blood transfusion. Despite an adequate increase in HIF-1 alpha CD39 and CD73 activity decreased significantly after aortic clamping (P = 0.047 and P = 0.016, respectively). Aortic clamping is associated with a clear and strong systemic inflammatory response and impaired repair mechanisms in terms of purinergic signaling. Patients undergoing open aorta repair could benefit from pre-operative medical therapy, which enhances CD73 expression.