Individuals with hypertension and sympathetic overactivity are at risk for cardiovascular events. Renin inhibitors are new while thiazide diuretics are first-class drugs used for treatment of hypertension. The purpose of this study was to determine whether 6 months of treatment with aliskiren (ALSK) or hydrochlorothiazide (HCTZ) would alter blood pressure (BP) and muscle sympathetic nerve activity (MSNA) indices in older mild hypertensives during a cold pressor test (CPT). We hypothesized that the ALSK group would demonstrate a blunted response compared to HCTZ. Nineteen (9 men, 10 women) subjects performed a CPT pre- and post treatment where heart rate (HR), systolic BP (SBP) and diastolic BP (DBP), and MSNA were measured. Blood samples were withdrawn for assessment of renal-adrenal hormones. Both medications lowered ambulatory SBP and DBP (P < 0.05). Direct renin tended to be higher in the ALSK group after treatment (P = 0.081). Aldosterone was higher in the HCTZ group after treatment (P < 0.001). As expected, both groups showed increases in HR, SBP, DBP, and MSNA during the CPT (all P < 0.05). All cardiovascular and MSNA responses were similar pre- and post treatment in both groups (peak CPT SBP: 26 ± 10 vs. 17 ± 21 and 21 ± 20 vs. 29 ± 15 mmHg for pre vs. post for HCTZ and ALSK, respectively; peak CPT MSNA burst frequency: 13 ± 8 vs. 11 ± 11 and 11 ± 17 vs. 6 ± 13 bursts/min; all P > 0.05). Treatment with these antihypertensive medications lowered BP but was not successful in lowering the responsiveness to the CPT.