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Cardiotoxicity is a well-recognized side effect induced by chemotherapeutic drugs such as anthracycline and trastuzumab through different mechanisms. Currently, accumulating evidence supports that dexrazoxane (DZR) can minimize the risk of cardiotoxicity. In this study, we investigated whether dexrzoxane could reduce cardiotoxicity in the treatment of anthracycline combined with trastuzumab.We randomly divided 90 experimental F344 rats into control group, chemotherapeutics and trastuzumab (doxorubicin [DOX] + herceptin [Her]) group, and chemotherapeutics, trastuzumab, and DZR (DOX + Her + DZR) group. Animal status and body weight, cardiac function, serum cardiac markers, cardiomyocyte apoptosis of the rats, and expression level of calpain-2 were evaluated. Left ventricular ejection fraction (LVEF) and fractional shortening (FS) of the left ventricle were observed. The serum levels of malondialdehyde (MDA) and cardiac troponin I (cTnI) and cardiomyocyte apoptosis were detected by enzyme linked immunosorbent assay and TdT-mediated dUTP nick end labeling assays. The mRNA and protein level of calpain-2 were measured by reverse transcriptase polymerase chain reaction and Western blot.We observed that the LVEF and FS of the left ventricle were significantly higher in the DOX + Her + DZR group than that in the DOX + Her group (P < 0.05). The serum levels of MDA and cTnI between DOX + Her group and DOX + Her + DZR group were significantly different. In addition, cardiomyocyte apoptosis in the DOX + Her + DZR group was significantly less severe than that in the DOX + Her group (P < 0.05). After DZR treatment, the calpain-2 mRNA and protein levels in the DOX + Her + DZR group were significantly higher than the DOX + Her group (P < 0.05).Our results suggest that DZR can effectively reduce the cardiotoxicity of combinatorial treatment of trastuzumab and anthracycline partly through upregulating calpain-2.