Sympathetic hyperactivity (SH) and renin angiotensin system (RAS) activation are commonly associated with heart failure (HF) even though the relative contribution of these factors to the cardiac derangement is less understood. The role of SH on RAS components and its consequences for the HF were investigated in mice lacking _2A and _2C adrenoceptors (_2A/_2CARKO) that present SH with evidence of HF by 7 months of age. Cardiac and systemic RAS components and plasma noradrenaline (PN) levels were evaluated in male adult mice at 3 and 7 months of age. In addition, cardiac morphometric analysis, collagen content, exercise tolerance, and hemodynamic assessments were made. At 3 months, _2A/_2CARKO mice showed no signs of HF while displaying elevated PN, activation of local and systemic RAS components and increased cardiomyocyte width (16%) compared to wild type mice (WT). In contrast, at 7 months, mice presented clear signs of HF accompanied only by cardiac activation of angiotensinogen and angiotensin II levels and increased collagen content (2 fold). Consistent with this local activation of RAS, 8 weeks of angiotensin II AT1 receptor blocker treatment restored cardiac structure and function comparable to the WT. Collectively, these data provide direct evidence that cardiac RAS activation plays a major role underlying the structural and functional abnormalities associated with a genetic SH induced HF in mice.