During percutaneous coronary interventions (PCI), a guidewire is used as an initial way of accessing a specific vasculature. There are varieties of guidewires on the market and choosing an appropriate one for each case is critical for a safe and successful intervention. The main objective of this study is to predict the behavior of the guidewire and its performance in a vasculature prior to the procedure. Therefore, we evaluate the effectiveness of different mechanical properties of the guidewire on its behavior. A two-dimensional (2D) model has been developed in which a guidewire is considered as a set of small rigid segments connected to each other by revolute joints. These joints have two degrees-of-freedom to allow rotation. Linear torsional springs and dampers are applied in each joint to account for the elastic properties of the guidewire; the elastic properties have been measured for two commercially available guidewires (Hi-Torque Balance Middleweight Universal II—Abbot and Amplatz Super Stiff—Boston Scientific) and these are used in the model. Only translational motion has been applied to the guidewires and the effect of bending stiffness of the guidewire and also friction between guidewire and vasculature on its behavior are investigated. The results are validated with actual movement of the guidewires in a simple phantom model. Behavior of a guidewire in a vasculature was predicted using the developed model. The results of both simulation and experiment show that the behavior of a guidewire is influenced by its mechanical properties and by the friction between the guidewire and vasculature. This study is the first step to develop a complete model, which can predict the behavior of a guidewire inside the vasculature. We compared the tip trajectory for two commercial guidewires in one vasculature geometry. In future, this kind of knowledge might support not only the interventionist in choosing the best suitable guidewire for a procedure but also the designer to optimize new instrument to have the desired behavior.