Objective To select more sensitive animal model to evaluate the cardiotoxicity of drugs, we used the heart-specific CYP2E1 genetically modified mice (α-MHC CYP2E1 transgenic mice [Tg(+) mice] and α-MHC CYP2E1 silencing transgenic mice [sTg(+) mice] ) to evaluate the drug sibutramine-induced cardiotoxicity. Methods The 8-week old male Tg(+), sTg(+), and C57BL/6 mice (wild type, WT), 50 mice in each group, were randomly divided into 5 groups: the solvent control group (intragastric gavage of pure drinking water), and the four sibutramine (50 mg/kg, 100 mg/kg, 150 mg/kg and 300 mg/kg) treatment groups, respectively. The general condition of the mice was observed and the survival rate was determined during the drug treatment period. At 15 days after the sibutramine administration, the blood biochemical indicators of cardiotoxicity lactate dehydrogenase (LDH), creatine kinase (CK), and creatine kinase isoenzyme (CK-MB) were assessed, and then the mice were sacrificed and heart tissue samples were taken for pathological examination and immunohistochemical observation of the expression of connexin 43 (CX43). Results (1) The blood biochemical indicators in the sibutramine 50 mg/kg and 100 mg/kg Tg(+) treated mice were significantly higher than those in the WT mice (P<0.05 or P<0.01), and significantly higher in the 50 mg/kg, 100 mg/kg and 150 mg/kg sibutramine treated Tg(+) mice than in the sTg(+) mice (P<0.05 or P<0.01). However, when the sibutramine was given at a dose of 300 mg/kg, the values of those indicators in the Tg(+) mice were significantly lower than that in the WT and sTg(+) mice (P<0.05 or P<0.01), with the lowest level in the sTg(+) mice. (2) The pathological examination revealed cardiotoxic changes in the Tg(+) and WT mice. (3) The immunohistochemical analysis showed that alongside with the increasing drug dose, the expression of CX43 was decreased in the intercalated disks of cardiomyocytes in the Tg(+), sTg(+) and WT mice, and the color staining intensity was mostly decreased in an order of Tg(+)>WT>sTg(+) mice. Conclusions Tg(+) mice may have a higher sensitivity in the evaluation of potential cardiotoxicity than WT mice, and sTg(+) mouse is a good model of protection against cardiotoxicity.