The mechanisms for the pleiotropic effects of statins are not well understood. A potential beneficial effect of statins in states that are characterized by enhanced sympathetic function such as chronic heart failure (CHF) is sympathoinhibition. The present study identifies one central mechanism that mediates the statin-induced sympathoinhibition in CHF. Statins can act by reducing reactive oxygen species directly and through an angiotensin II–NADP(H) oxidase mechanism. Here we show that in one of the most important central areas for modulation of sympathetic outflow, the rostral ventrolateral medulla, simvastatin causes a decrease in angiotensin II type 1 receptors, NAD(P)H oxidase protein, and reactive oxygen species in an animal model of CHF. Several of the protein subunits that are necessary for NAD(P)H oxidase activity were downregulated in animals treated with simvastatin for approximately 1 month. These results have important implications for understanding the sympathetic neural abnormalities that occur in the CHF state. Furthermore, these data suggest that statin treatment may be beneficial for heart failure patients by breaking the angiotensin II–sympathetic nerve activity positive feedback that results in deterioration of peripheral cardiovascular function.