Background: In breast cancer patients, the administration of Trastuzumab and Doxorubicin is associated with an increased risk of cardiotoxicity. The aim of the study was to determine if the antioxidant probucol would be useful in attenuating this drug induced cardiotoxicity. Methods: In an acute murine model of chemotherapy induced cardiomyopathy, wild-type C57Bl/6 mice received one of the following regimens: (1) control; (2) doxorubicin; (3) trastuzumab; (4) dox+trastuzumab; (5) probucol; (6) probucol +dox; (7) probucol+trastuzumab; (8) probucol+dox+trastuzumab. Serial murine echocardiography with tissue Doppler imaging was performed daily. Histological and biochemical studies were conducted at day 10 of the experiment. Results: Mice treated with prophylactic probucol demonstrated minimal cardiotoxicity compared with those treated with doxorubicin+trastuzumab. Survival rate was only 27% at day 3 of the experiment in the doxorubicin+trastuzumab group compared to 82% of mice receiving probucol+ doxorubicin+trastuzumab. Survival, apoptosis and histological remodeling were preserved in mice prophylactically treated with probucol following the administration of trastuzumab+doxorubicin. Conclusion: The synergistic cardiotoxicity of trastuzumab plus doxorubicin is attenuated by the antioxidant probucol.