Background - There is compelling experimental evidence that autologous skeletal muscle (SM) cell transplantation improves postinfarction cardiac function. This study assessed whether this benefit is still manifested in the clinically relevant setting of a treatment by ACE inhibitors. Methods and Results - a myocardial infarction was created in 99 rats by coronary artery ligation. They were divided into 4 groups. Two groups did not receive any drug and were intramyocardially injected 7 days after the infarct with either culture medium alone (control rats, n=16) or autologous SM cells (2.3×106 myoblasts) previously expanded ex vivo for 7 days (myoblasts, n=24). Two other groups received the ACE inhibitor perindoprilat (1 mg · kg-1 · d-1), started the day of the infarct and continued uninterruptedly thereafter, and underwent time-matched procedures, that is, they were intramyocardially injected at 7 days after infarction with either culture medium alone (ACE inhibitors, n=22) or autologous SM cells (2.5×106 myoblasts) previously expanded ex vivo for 7 days (ACE inhibitors+myoblasts, n=37). Left ventricular function was assessed by 2D echocardiography. At the end of the 2-month study, left ventricular ejection fraction (%, mean±sem) was increased in all groups (myoblasts, 37.4±1.2 ACE inhibitors, 31.6±1.7; ACE inhibitors+myoblasts, 43.9±1.4) compared with that in control rats (19.8±0.7) (p<0.0001). The improvement in ejection fraction was similar in the Ace inhibitor and the myoblast groups (31.6±1.7 versus 37.4±1.2, P=0.0636). However, in the ACE inhibitor+myoblast group, this improvement was greater than that seen in hearts receiving either treatment alone (43.9±1.4 versus 31.6±1.7 in the ACE inhibitor group and 43.9±1.4. versus 37.4±1.2 in the myoblast group, P<0.0001 and P=0.0084, respectively). Conclusions - These data provide further support for the clinical relevance of autologous SM cell transplantation in that its cardioprotective effects are additive to those observed with ACE inhibitors.