Objective To investigate the protective effect and safety of amiloride, a potassium-sparing diuretic, on the injured heart in senile SD rats with long term rosiglitazone treatment and study the possible underlying mechanism. Methods Forty senile rats were divided into 4 groups: control group, rosiglitazone treatment group [10mg/(kg·d)], amiloride treatment group [5mg/(kg·d)], and combined treatment group (dose as the single treatment group), with 10 rats in each group. The rats received intra-gastrical administration for 6 months after delactation at 2 weeks old. Blood and urinary electrolytes, renal function, blood glucose and blood lipids were measured every month. The heart function was evaluated by heart ultrasonography in the end of 6 months treatment. Pathological changes in the heart, liver and kidneys were observed with hematoxylin-eosin (HE), periodic acid-Schiff (PAS) and Masson staining after the rats were sacrificed. The effect of rosiglitazone and amiloride on above indices were studied. Results In 6 months after the treatment, the serum sodium was obviously increased in rosiglitazone treatment group, but that in the combined treatment group stood between the rosiglitazone treatment group and normal control. Ultrasound examination showed that left ventricular posterior wall thickness systolic (LVPWTs) and diastolic (LVPWTd), and interventricular septal thickness systolic (IVSTs) and diastolic (IVSTd) were increased in the rosiglitazone treatment group, but there was no difference in these indices between the combined treatment group and the control group. Myocardial damages were found in rosiglitazone treatment group, but none in the combined treatment group. Conclusion Rosiglitazone aggravate the myocardial damages, while amiloride should be used to relieve the side effect of rosiglitazone.