Cardiac pacing initiated from epicardial or transvenous apical right ventricular electrodes causes asynchronous ventricular contraction. This alters myocardial stress vectors and results in adverse cellular and subcellular changes in the experimental animal. Clinically, such changes may contribute to the adverse hemodynamics reported with long-term ventricular pacing. To determine the feasibility of direct stimulation of the ventricular specialized conduction systems and therefore the potential for maintenance of normalized depolarization patterns, 13 beagle puppies were studied. Baseline ventricular activation and contraction patterns were obtained using intracardiac electrograms and multigated nuclear acquisition (MUGA) imaging. Septal electrode insertion from the aortoatrial groove was accomplished by use of two-dimensional echocardiography and continuous electrocardiographic (ECG) monitoring of the surface ECG during pacemaker implantation in five puppies. Standard right ventricular epicardial electrodes were implanted in five additional animals, with three remaining as age-matched non-paced controls. After 4 months of observation, repeat MUGA imaging and intracardiac electrograms demonstrated nearly normal biventricular activation and contraction patterns among the septal-paced group. Histopathologic examination illustrated normal cellular morphology in the septal-paced animals. This study demonstrates that pacing electrode insertion into the proximal interventricular septum is feasible and results in utilization of the normal ventricular conduction pathway. Such an approach to initiation of ventricular stimulation may attenuate the adverse effects of long-term ventricular pacing.