We studied the effects of extremely low-dose human renin inhibition (aliskiren) with low angiotensin II receptor blockade (losartan) in a novel double-transgenic rat model harbouring both human renin and angiotensinogen genes. We found that low-dose aliskiren and low-dose losartan effectively reduced mortality and target-organ damage with minimal, non-significant, effects on blood pressure (BP). Our data suggest that renin-angiotensin system (RAS) inhibition ameliorates target-organ damage in an Ang II-driven model of hypertension. Direct renin inhibition is equally efficacious in this regard. Our study does not fully answer the question of BP-lowering versus RAS inhibition. This question is important and was at least partially addressed with our low-dose model.