High-frequency mechanical vibrations (20-50 kHz), delivered via small diameter flexible wire waveguides represent a minimally invasive technology for the treatment of chronic total occlusions and in other tissue ablation applications. Tissue disruption is reported to be caused by repetitive mechanical contact and cavitation. This work focuses on the effects of vibrating wire waveguides in contact with arterial tissue. An apparatus with clinically relevant parameters was used, characterized as operating at 22.5 kHz and delivering amplitudes of vibration of 17.8-34.3 μm (acoustic intensity, I(SATA): 1.03-3.83 W/cm(2)) via 1.0-mm diameter waveguides. Inertial cavitation (in water at 37 °C) was determined to occur above amplitudes of vibration greater than 31.4 μm (I(SATA) = 3.21 W/cm(2)). The energized waveguides were advanced through tissue samples (porcine aorta) and the force profiles were measured for a range of acoustic intensities. The results show that the tissue perforation initiation force, perforation initiation energy, and total energy required to perforate the tissue reduces with increasing acoustic intensity. No significant reduction in perforation force or energy was observed in the inertial cavitation region. Multistage perforation was evident through the force profile and histological examination of the tissue samples post wire waveguide perforation.