The endothelial function declines with age and dyslipidemia (DL) has been shown to hasten this process by favoring the generation of reactive oxygen species (ROS). Cyclooxygenase-2 (COX-2) can be induced by ROS, but its contribution to the regulation of the endothelial function is unknown. Since COX-2 inhibitors may be deleterious to the cardiovascular system, we hypothesized that DL leads to ROS-dependent endothelial damage and a protective up-regulation of COX-2. Dilations to acetylcholine (ACh) of renal arteries isolated from 3, 6 and 12 m/o wild type (WT) and DL mice expressing the human ApoB-100 were recorded with or without COX inhibitors and the antioxydant N-acetyl-L-cystein (NAC). NO and EDHF were inhibited using L-NNA and a depolarizing solution, respectively. In WT mice, the dilation to ACh declined at 12 months but was insensitive to COX-1/2 inhibition alone or with NAC. DL led to an early endothelial dysfunction at 6 m/o, normalized however by NAC. At 12 m/o, vascular sensitivity to ACh was further reduced by DL. At this age, selective COX-2 inhibition reduced the dilation, while addition of NAC improved it. In 3 and 6 months old WT mice, L-NNA significantly reduced the dilation, while it limited the dilation only in 3 m/o DL mice. EDHF-dependent dilation remains identical in both groups. These data suggest that COX-2 activity confers endothelium-dependent vasodilatory function in aged DL mice in the face of a pro-oxidative environment. Up-regulation of this pathway compensates for the early loss of the contribution of NO in DL mice.