To investigate the effect of Pioglitazone (Pio) on the rejection reactions that occurs in heart transplantation. A total of 96 rats with heart transplantation were treated with cyclosporin A (CsA) alone, Pio alone, or the combination of both. The percentages of CD25+ and CD28+ T cell in the spleen of rats were measured using flow cytometry. Combined use of Pio and CsA prolonged the survival of transplanted hearts. In addition, pathologic lesions were relieved. Meanwhile, the contents of interleukin-2 in serum and the percentages of CD25+ and CD28+ lymphocytes in the receptor’s spleens were significantly reduced by the combination of Pio and CsA. Of note, the effect of combined use of Pio and CsA was better than that of single use. The present study demonstrates that combined use of Pio and CsA reduces the dose of CsA, ameliorates rejection reactions, and improves the life quality of recipients with heart transplantation.