OBJECTIVE Cardiomyocyte apoptosis is one of the pathologic phenomena associated with diabetes and related conditions including obesity, insulin resistance and hyperlipidaemia. In the present study, the protective effects of pioglitazone on cardiomyocyte apoptosis was evaluated in experimental diabetes induced by low dose of streptozoticin (STZ) combined with high fat diet (HFD) in rats. METHODS Male Wistar rats (150-200 g) were injected with low-dose STZ (45 mg/kg, i.v., single dose) and orally fed with a HFD (20 g/day/rat) for a period of 28 days and simultaneously treated with pioglitazone (20 mg/kg/p.o.) for a period of 21 days (from 8 th day to 28 th day). On 29 th day blood was collected, serum separated and used for biochemical parameters. Heart tissue was used for cardiomyocyte apoptosis measurement and also for histopathological examination. RESULTS Pioglitazone treatment resulted in a decrease in cardiomyocyte apoptosis as revealed by a decrease in cardiac caspase-3, lactate dehydrogenase (LDH) levels and DNA fragmentation, and an increase in Na+K+ATPase levels in diabetic rats. Cardiac histology of diabetic control rats showed dense focal fatty infiltration in the myocardial cells whereas normal architecture with regular morphology and well preserved cytoplasm was observed with pioglitazone treatment. Pioglitazone treatment significantly reduced the heart rate, mean arterial blood pressure, body mass index (BMI) and levels of serum glucose, leptin, insulin, HOMA-IR, total cholesterol (TC) and triglycerides (TGs), apoliproprotein-B glycosylated haemoglobin (HbA1c) levels and atherogenic index, and increased the levels of serum high density lipoprotein cholesterol (HDL-C) and cardiac antioxidant enzymes. CONCLUSIONS The present study results suggest that pioglitazone possesses cardiac anti-apoptotic potential in diabetic rat model and can be further explored for its use for treatment of diabetic cardiomyopathy.