The specific antagonists of tumor necrosis factor- (TNF-) infliximab and etanercept are established therapeutical agents for inflammatory diseases such as rheumatoid arthritis or Crohn's disease. While the importance of TNF- in chronic inflammatory diseases is well established, little is known about its implications in the cardiovascular system. Since the proliferation of arteriolar connections towards functional collateral arteries (arteriogenesis) is an inflammatory-like process, we tested in vivo the hypothesis that infliximab and etanercept hold anti-arteriogenic actions. Sixty-three New Zealand White rabbits underwent femoral artery occlusion and received infliximab, etanercept or vehicle according to clinical dosage regimes. After one week, collateral conductance was assessed with fluorescent microspheres and revealed a significant inhibition of arteriogenesis (collateral conductance [ml/min/100mmHg]: PBS: 52.4±8.1, infliximab: 35.2±7.7, etanercept: 33.3±10.1; P<0.001). High-resolution angiography showed no significant differences in number of collateral arteries, but immunohistochemical analysis demonstrated a decrease in mean collateral diameter, vascular smooth muscle cell proliferation and reduced leukocyte accumulation around collateral arteries in the treated groups. Infliximab and etanercept were shown to bind to infiltrating leukocytes, which are important mediators of arteriogenesis. Infliximab induced monocyte apoptosis, and both substances did not affect monocyte expression of the adhesion molecule Mac-1. We demonstrated that TNF- serves as a pivotal modulator of arteriogenesis, which is attenuated under treatment with TNF- inhibitors. Reduction of collateral conductance is most likely due to an inhibition of perivascular leukocyte infiltration and subsequent lower vascular smooth muscle cell proliferation. This is the first report showing a negative influence of TNF- inhibitors on collateral artery growth.