Doxorubicin (DOX) is commonly used as an anti-cancer agent. However, its severe cardiotoxicity often makes it life threatening even long after DOX therapy during childhood. We recently reported interferon-γ (IFN-γ) necessary for DOX-induced acute cardiotoxicity in a p38 dependent way and, asked here for the potential of IFN-γ blockade to prevent DOX-induced chronic cardiotoxicity during tumor therapy. In our model system, mice without or with growing tumors repeatedly received DOX treatment. Simultaneous injection of anti-IFN-γ antibody R46-A2 with DOX to block IFN-γ signal efficiently protected the cardiac function of DOX treated recipients. Importantly, a single late injection of R46-A2 after DOX exposure also ameliorated DOX induced cardiac dysfunction in tumor-bearing mice. The anti-IFN-γ treatment did not affect the DOX-mediated tumor suppression effect and it left the main cellular immune response intact. Therefore, temporary blockade of IFN-γ may represent a novel strategy to ameliorate established DOX induced cardiotoxicity (DIC) or prevent its development in tumor therapy.