For a limited range of exposure parameters, pulsed high intensity focused ultrasound (HIFU) has been shown to increase the delivery of certain systemically administered macromolecular diagnostic and therapeutic agents in mice. The mechanism for the enhanced delivery has not been demonstrated definitively and, in principle, can include thermal, cavitational, and non-cavitation mechanical effects. The sonicated tissue has no damage on histology. As a step towards clinical translation, the safety of this technique needs to be assessed in a clinically relevant manner. In this study, the safety of pulsed HIFU is evaluated with near real-time phase shift magnetic resonance (MR) thermometry and anatomic MR imaging using rabbits as subjects. MR guidance enables pulsed HIFU enhanced delivery to be implemented safely from a thermal standpoint. Although the effects of pulsed HIFU are not seen on anatomic MR images, they may be detected on MR sequences sensitive to permeability, diffusion, and elasticity. Such work that may optimize pulsed HIFU enhanced delivery is in progress.