Current methods of cardiac gene transfer include intramuscular injection (im) into heart muscle or coronary delivery. When applied to rodents with heart failure, these surgical approaches are associated with high mortality, an impediment that would also complicate clinical studies. To circumvent this, we selected a transgene, Insulin-like Growth Factor-I (IGF-I), which may have favorable effects on heart function when secreted from a remote site. This study examines the feasibility of skeletal muscle injection of adeno-associated virus-5 encoding IGF-I under tet regulation (AAV5.IGFI-tet). Left coronary ligation was performed in rats and MI confirmed 1wk later by echocardiography. Rats with MI then received 2×1012 vp of AAV5.IGFI-tet in the anterior tibialis (im). Four wks later they were randomly assigned to receive doxycycline in the drinking water (IGF-On; n=5) or not (IGF-Off; n=3). Ten wks post MI anesthetized rats underwent a final echo and terminal study in which a 1.8F pressure-volume transducer was placed in the left ventricle (LV). IGF-On rats showed an increased in LV fractional area change (p=0.04), ejection fraction (p=0.04), and velocity of circumferential fiber shortening (p=0.04), and had smaller LV end-diastolic (p=0.002) and end-systolic (p=0.003) dimensions. LV function was improved with dobutamine infusion (Table; IGF-On, n=4; IGF-Off, n=3). Serum IGF-I was increased 5 wk after activation (IGF-On: 218±7 ng/ml; IGF-Off: 158±24 ng/ml; p=0.046). These data indicate that intramuscular injection of AAV5.IGFI-tet increases function of the failing heart.