Background: A previous study has demonstrated that orally administered atorvastatin reduces sympathetic nervous system (SNS) activation via an anti-oxidant in the rostral ventrolateral medulla (RVLM) of hypertensive rats, whereas amlodipine did not. Furthermore, several previous reports have suggested that atorvastatin or amlodipine improves cognitive dysfunction during hypertension. The aim of the present study was to determine whether a combination of atorvastatin and amlodipine causes sympathoinhibition via reduction of oxidative stress in the RVLM and improves cognitive dysfunction of hypertensive rats. Methods and Results: Stroke-prone spontaneously hypertensive rats (SHRSPs), as a hypertensive model with sympathoexcitation, were divided into 4 groups; a combination of atorvastatin and amlodipine-treated (COM), atorvastatin-treated (ATR), amlodipine-treated (AML), hydralazine-treated (HYD), and vehicle-treated SHRSPs (VEH). After treatment for 28 days, the mean blood pressure did not change in ATR rats, and was reduced to the similar levels in COM, AML, and HYD rats. However, SNS activation and oxidative stress in the RVLM were significantly lower only in COM than in ATR, AML, HYD, and VEH rats. Cognitive performance and manganese-superoxide dismutase activity in the hippocampus were significantly higher, and oxidative stress in the hippocampus was significantly lower in COM than in VEH, AML, and HYD rats to a greater extent than in ATR rats. Conclusions: A combination of atorvastatin and amlodipine causes sympathoinhibition via an anti-oxidant in the RVLM and improves cognitive dysfunction via an anti-oxidant in the hippocampus in hypertensive rats, independent of the blood pressure-lowering effect.  (Circ J 2012; 76: 1934–1941)