Advanced glycation end products (AGEs) and dendritic cells (DCs) are believed to play a key role in the development and progression of cardiovascular diseases. However, their role and interactive mechanism remain uncertain. The aim of the present study is to investigate the mechanism of AGE- and DC-mediated heart failure. Time- and dose-dependent western blot and immunohistochemical analysis showed a significant upregulation in the expression of AGEs, receptor for AGEs (RAGE), and OX-62. Further hemodynamic and echocardiogram analysis revealed that AGEs mediate cardiac failure. Treatment with pioglitazone improved heart function by decreasing the expression of AGEs and OX-62 in the rats with myocardial infarction (MI) plus diabetes. AGEs induced the maturation of DCs in both time- and concentration-dependent manner with upregulation in RAGE and dendritic markers. Further, coculture of cardiomyocytes with DCs in the presence of AGEs significantly upregulated hypertrophy-associated genes as determined by real-time PCR. In conclusion, the present study shows clear evidence that AGEs promote heart failure via the maturation of DCs. In addition, inhibition of AGEs by pioglitazone alleviates accumulation of DCs and thus improves heart function.