The purpose of this study was to design and evaluate a system to test the mechanical behavior of pacemaker and defibrillator leads. Over 300,000 pacemaker and implantable cardioverter defibrillator (ICD) procedures are performed every year in the U.S. for the treatment of cardiac arrhythmias, ventricular dysrhythmias, and congestive heart failure. These procedures require implanting transvenous leads into the interior wall of the heart. A serious and sometimes fatal complication that may occur during or after lead implantation is perforation of the lead tip through the heart wall. The factors that lead to perforation are not fully understood. This illustrates that the mechanical interactions between the lead tip and the cardiac tissue need to be further investigated to improve the outcome for pacemaker and ICD patients. To improve the performance of lead tips, the testing protocols must reproduce physiological and clinically relevant tip-tissue interactions. As a first step toward this goal, testing parameters that influence those interactions must be identified. We investigated the effect of test system parameters, which reproduce potentially critical physiological constraints, on the load experienced at the distal tip of thirteen pacemaker and defibrillator active-fixation leads. We evaluated the use of a constraint to simulate the effect of the right ventricle (RV constraint) in vivo, how and where the lead was fixed in the test configuration, location of the load cell in the test system, rotation and frequency of the test protocol, and the effect of stylets. Results showed the RV constraint and load cell placement had the largest impact on lead tip load, while rotation of the test setup and test frequency had a minimal impact. Recommendations are made for a test system and protocol for in vitro testing of leads that take into consideration in vivo conditions. Better approximations of the in vivo environment may lead to improved product development. The potential of this system to more effectively evaluate new pacemaker and defibrillator lead designs will require further study.