Cardiac hypertrophy is not only an adaptational state before heart failure but also is an independent risk factor for ischemia, arrhythmia, and sudden death. However, the direct effects of hypercholesterolemia on the myocardium and mechanisms are not completely understood. It has been demonstrated that peroxisome proliferator-activated receptor-γ (PPARγ) ligand agonists attenuate cardiac hypertrophy through anti-inflammatory effects. The present study investigated the effects of PPARγ agonists on hypercholesterolemia-dependent, renin-angiotensin-system-related cardiac hypertrophy. The findings showed that left ventricular hypertrophy, eminent cardiomyocyte hypertrophy, and lipid deposits in myocardium were observed in the rats fed a cholesterol-rich diet for 6 months, while these characteristic pathological alterations and the increase in angiotensin II (ANG II) level and over-expression of angiotensin II type 1 receptor (AT1R) in the left ventricular tissues induced by the cholesterol-rich diet were significantly suppressed to equal extents by rosiglitazone and irbesartan. In contrast, expression of angiotensin II type 2 receptor (AT2R) was upregulated by these two drugs. In addition, lipid metabolism was markedly improved. The above findings suggest that the cardioprotection of the PPARγ agonist against cardiac hypertrophy evoked by hypercholesterolemia in rats is mediated partially by the improvement of lipid profile, the reduction of ANG II level in the local tissue along with the downregulation of AT1R expression, and upregulation of AT2R expression. Copyright © 2009 John Wiley & Sons, Ltd.