Aging is associated with alterations in vascular homeostasis, including a reduction in flow-mediated vasodilation, which in women is related to the onset of menopause. We previously found that in female animals, aging is associated with an increase in Tumor Necrosis Factor (TNF). Thus, we investigated the role of in vivo TNF inhibition on vascular responses to shear stress in aging female rats. Methods and Results: Mesenteric arteries (~ 150 microns) were isolated from young (3 months) and ovariectomized Sprague Dawley female rats approaching reproductive senescent (12 months) treated either with placebo or a TNF inhibitor (Etanercept; 0.3 mg/kg) and were mounted on a pressure myograph system. Vessels were equilibrated at an intraluminal pressure of 60 mmHg, and then pre-constricted with phenylephrine at ~ 70% of their initial diameter. Perfusate flow was increased in steps from 0 to 150 µL/min. Compared with young, aged vessels have a decrease in flow-mediated dilation (maximal dilation (mean ± SE): 52 ± 4 vs. 24 ± 15 %; P<0.05), which was improved by TNF inhibition. Moreover, in aged vessels maximal dilation to flow was achieved at higher levels of shear stress compared with young vessels. In all groups, flow-mediated dilation was abolished by either endothelial removal or NO synthase inhibition with L-NAME. However, the modulation by L-NAME was reduced in vessels from aged animals compared with young animals, but was improved in the Etanercept treated aged animals. Conclusions: In vivo chronic TNF inhibition improves flow-mediated arterial dilation in resistance arteries of aged female animals.