Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. We have previously reported that glucan phosphate (GP) significantly increased survival in a murine model of cecal ligation and puncture (CLP)-induced sepsis. In the present study, we examined the effect of GP on cardiac dysfunction in CLP-induced septic mice. GP was administered to ICR/HSD mice 1 hr before induction of CLP. Sham surgical operated mice served as control. Cardiac function was significantly decreased six hrs after CLP-induced sepsis compared with sham control. In contrast, GP administration prevented CLP-induced cardiac dysfunction. Macrophage migration inhibitory factor (MIF) has been implicated as a major factor in cardiomyocyte apoptosis and cardiac dysfunction during septic shock. CLP increased myocardial MIF expression by 88.3% (p<0.05) and cardiomyocyte apoptosis by 7.8 fold (p<0.05) compared with sham control. GP administration, however, prevented CLP-increased MIF expression, and decreased cardiomyocyte apoptosis by 51.2% (p<0.05) compared with untreated CLP mice. GP also prevented sepsis-caused decreases in phospho-Akt, phospho-GSK-3 and Bcl-2 levels in the myocardium of septic mice. These data suggest that GP treatment attenuates cardiovascular dysfunction in fulminating sepsis. GP administration also activates the PI3K/Akt pathway, decreases myocardial MIF expression and reduces cardiomyocyte apoptosis.