Abstract: Doxorubicin (Dox), a potent anti-cancer drug, can cause cardiac dysfunction and failure. Endogenous Fibroblast Growth Factor-2 (FGF2), a protein implicated in cardioprotection, regulates cardiac vulnerability to Dox. In wild type mice and in humans, cardiac FGF2 is composed of a mixture of mostly high (Hi-) but also low (Lo) molecular weight isoforms and is produced mainly by non-myocytes. We compared wild type mice, FGF2(WT), to mice genetically engineered as to express: no FGF2, FGF2(?); only Hi-FGF2, FGF2(Hi); only Lo-FGF2, FGF2(Lo). Sole expression of endogenous L0-FGF2 in vivo, or by fibroblasts in vitro, protects cardiomyocytes from Dox. In a wild type environment, neutralization of endogenous Hi-FGF2 presents a potential prophylactic treatment against Dox-induced cardiotoxicity.