Mercury increases the risk of cardiovascular disease, oxidative stress and alters vascular reactivity. This metal elicits endothelial dysfunction as a result of the decreased NO bioavailability by increased oxidative stress and contractile prostanoids production. NADPH oxidase is the major source of reactive oxygen species (ROS) in the vasculature. Our aim was to investigate whether treatment with apocynin, a NADPH oxidase inhibitor, prevents the vascular effects caused by chronic intoxication by low concentrations of mercury. Three-month-old male Wistar rats were treated for 30 days with: a) intramuscular injections – i.m. – of saline; b) HgCl2 (i.m. 1st dose 4.6 μg/kg, subsequent doses 0.07 μg/kg/day); c) Apocynin (1.5 mM in drink water plus saline i.m.); d) Apocynin plus HgCl2. Mercury treatment: 1) increased aortic vasoconstrictor response to phenylephrine and reduced endothelium-dependent responses to acetylcholine; 2) increased the involvement of ROS and vasoconstrictor prostanoids in phenylephrine response whereas reduced the endothelial NO modulation of such responses, 3) reduced aortic activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) and increased plasma malondialdehyde (MDA) levels. Treatment with apocynin partially prevented the increased phenylephrine responses and reduced the endothelial dysfunction elicited by mercury treatment. In addition, apocynin treatment increased NO modulation of vasoconstrictor responses and aortic SOD activity and reduced plasma MDA levels, without affecting the increased participation of vasoconstrictor prostanoids observed in aortic segment from mercury treated rats. Conclusions: Mercury increases the vasoconstrictor response to phenylephrine by reducing NO bioavailability and increasing the involvement of ROS and constrictor prostanoids. Apocynin protects the vessel from the deleterious effects caused by NADPH oxidase, but not from those caused by prostanoids, demonstrating a two-way action.