Background - Transplantation of fetal cardiomyocytes has been shown to improve function of regionally infarcted myocardium, but its effects on global heart failure are still unknown. Methods and Results - Heart failure was induced in female mice by intraperitoneal injection of doxorubicin (2 mg/kg twice per week over 2 cycles of 2 weeks separated by a 2-week drug- free period). One week after the end of treatment, left ventricular function was assessed by transthoracic echocardiography (baseline). Animals were then randomized into 3 groups: The treated group (n=12) received an intramyocardial injection of fetal cardiomyocytes (1 x 106 in 10 μL) harvested from transgenic mice expressing the gene of β-galactosidase, the control group (n= 15) received an equivalent volume of culture medium alone, and 10 sham mice had no surgery. Two weeks and 1 month after transplantation, function was again assessed echocardiographically. At baseline, fractional shortening was not significantly different between the 3 groups. It then significantly increased in cell-treated mice at 2 weeks and 1 month after transplantation (P<0.002 and P<0.03 versus baseline, respectively), whereas it did not change in untreated animals. Transplanted cells could not be identified by β-galactosidase activity or presence of Y chromosome (with 1 exception). Conclusions - Cellular transplantation can improve function of globally failing hearts by a mechanism that might not necessarily involve the sustained presence of transplanted cells but rather the effects of cardioprotective factors released by them.