Given sufficient nuclei, inertial cavitation can greatly enhance heating rates during HIFU application. In the absence of bubble shielding effects, one might assume that increasing the driving pressure amplitude will serve to enhance both the temperature elevation and the amount of cavitation activity. Here we report on measurements in agar-graphite phantoms that show that during HIFU application, cavitation dose and temperature rise do increase with increasing pressure but only to a point where there is a measurable decrease in the 2.5–3-MPa range followed by further increase with higher pressures. This behavior can be predicted using single-bubble dynamics with allowed equilibrium bubble sizes that are consistent with waterlike viscosity values for an effective Newtonian fluid host [see Yang et al., J. Acoust. Soc. Am. 116, 3423–3431 (2004) for details]. These results can serve to help guide an optimal pressure as well as develop a further understanding of the bubble parameters and energy dissipation mechanisms involved in HIFU. [Work supported by the Dept. of the Army (Award No. DAMD17-02-2-0014) and the Center for Subsurface Sensing and Imaging Systems (NSF ERC Award No. EEC-9986821).]