We have shown previously that combined HMG-CoA reductase inhibitor (statin) and angiotensin II receptor blocker (ARB) therapy significantly improves both symptoms and left ventricular (LV) function over time in patients with heart failure (HF) by a clinical study [HF-COSTAR Trial]. We elucidated the mechanisms of combination therapy with the ARB (losartan, LOS) and long-acting and statin (simvastatin, SIM) for the treatment of load-induced heart failure. Salt-loaded Dahl salt-sensitive (DS) rats were treated with vehicle, LOS (5mg/kg/day), SIM (2mg/kg/day) and LOS + SIM for 16 weeks. LOS and SIM in combination improved LV dysfunction (ΔLV fractional shortening; LOS = 60%, SIM = 42%, LOS + SIM = 24%, p<0.05), limited LV hypertrophy (ΔLV septal thickness; LOS = −21%, SIM = −18%, LOS + SIM = −13%, p<0.05) and reduced cardiac fibrosis (ΔLV collagen density; LOS = −26%, SIM = −16%, LOS + SIM = −28%, p<0.05) more than LOS or SIM alone. Both Rho and matrix metalloprotease-9 (MMP-9) activity in LV tissue were increased in untreated DS rats, and LOS and SIM in combination decreased these changes more than did LOS and SIM monotherapies. We confirmed that the plasma level of Exp-3174 (E3174), a LOS metabolite and a potent inverse agonist of angiotensin II receptor type 1, was higher in rats treated with LOS and SIM in combination than in those treated with LOS alone (E3174/LOS ratio; LOS = 2.6 ± 0.3 vs. LOS + SIM = 3.2 ± 0.2, p<0.05). Next, to mimic the response of volume-overload heart failure in vitro, cultured neonatal rat cardiomyocytes (CMs) were cyclically stretched. Stretch-induced increased CM hypertrophy was suppressed by pretreatment with both SIM and E3174 more than by pretreatment with LOS, E3174, SIM, or LOS and SIM in combination. Mechanical stretch also induced activation of extracellular signal regulated kinase (ERK) and the stretch-induced ERK activation of CMs was also significantly suppressed by SIM + E3174. In conclusion, LOS and SIM had beneficial myocardial effects in rats with salt-sensitive hypertension, partly through promoting the accumulation of plasma E3174. SIM enhanced the myocardial protective effects of LOS through suppression of Rho and MMP-9 activity. Thus, a combination of ARB with statin has a promising potential as a therapeutic strategy for HF.