Objective: To investigate the effect of pioglitazone on high-fat (HF)-diet-induced left ventricular (LV) hypertrophy and dysfunction in rats. Methods: A total of 36 male Sprague-Dawley rats were randomly divided into 3 groups, namely, control, HF diet, and pioglitazone treatment group. High-fat diet group (HF group) animals were treated with HF diet for 30 weeks, whereas pioglitazone group was treated with HF diet for 30 weeks and pioglitazone in the last 6 weeks of the 30-week treatment. Fasting plasma free fatty acids (FFAs), serum, and myocardial triglyceride were measured. Left ventricular function was assessed by echocardiography. Renin, angiotensin II, and angiotensin types 1 and 2 (AT1/AT2) receptors in the myocardium were analyzed by immunohistochemistry and real-time polymerase chain reaction (PCR). Results: Systolic blood pressure, plasma FFA, serum, and myocardial triglyceride concentrations in HF group were higher than in control and pioglitazone groups (P < .01). There was no significant difference in LV weight index and LV posterior wall thickness between HF and pioglitazone groups; both were higher than in the control group (P < .01). Left ventricular ejection fraction, fraction of shortening, and cardiac index in HF group were lower than in the control and pioglitazone groups (P < .05). Myocardial expression of angiotensin II and AT1 receptor protein in HF group was higher when compared with the control and pioglitazone groups (P < .01). Myocardial renin and angiotensin II messenger RNA (mRNA) in HF group was also higher when compared with the control and pioglitazone groups, whereas the expression of AT2 mRNA was lower (P < .01). Conclusion: Pioglitazone diminished HF-diet-induced LV dysfunction. These effects may be related to a reduction in blood pressure, myocardial triglycerides sedimentary, and suppression of renin-angiotensin system.