This study aimed to determine the role of the renin-angiotensin system (RAS) in high-salt (HS) diet-induced left ventricular hypertrophy (LVH). Swiss mice were subjected to regular salt (RS) diet (0.6% NaCl), HS diet (4% NaCl), and HS plus irbesartan (50 mg/kg/day) or ramipril (1 mg/kg/day). After 8 weeks, arterial pressure was similar in all groups and similar to baseline, whereas left ventricle/body weight ratio was higher in HS mice than in RS mice (P < 0.005). There were also significant increases in collagen density, angiotensin-converting enzyme activity, angiotensin II type 1 receptor (AT1 receptor) density, and extracellular signal-regulated kinase (ERK1/2) phosphorylation in the left ventricle. Interestingly, increases in wall thickness and ERK1 phosphorylation were more marked in the septum than in the rest of the left ventricle. Irbesartan or ramipril treatment prevented LVH and the increase in ERK phosphorylation and reduced collagen content and AT1 up-regulation but up-regulated AT2 receptors. In normal mice, HS diet induces septum-predominant LVH and fibrosis through activation of the cardiac RAS-ERK pathway, which can be blocked by irbesartan or ramipril, indicating a key role of the cardiac RAS in HS diet-induced LVH.