Methods were investigated to acoustically control the extent to which cavitation-mediated tissue homogenization is responsible for lesion formation in vitro. These results may guide potential therapeutic procedures that induce damage predominantly via mechanical disruption and, thereby, avoid limitations associated with thermal ablative modalities. Porcine myocardium was insonified at 750 kHz using pulse sequences consisting of high-amplitude pulses (22 MPa Pr) interleaved with variable-amplitude "sustaining" pulses (e.g., 6.9 MPa Pr), which were intended to provide sufficient acoustic input to maintain cavitation activity between primary pulses, but to increase the spatial peak temporal average intensity (I(SPTA)) only marginally. Using modest temporal-average intensities (e.g., I(SPTA) approximately 200 W/cm2), approximately 0.5 cm3 lesions were produced consisting of homogenate that could be irrigated away to reveal smooth cavities. The prevalence of homogenate in a given lesion was sensitive to both pulse-repetition frequency and sustaining pulse amplitude, suggesting the existence of optimum acoustic parameters for producing homogenized lesions largely via mechanical perturbation.