High-intensity focused ultrasound (HIFU) has been shown to generate lesions that destroy brain tissue while disrupting the blood-brain barrier (BBB) in the periphery of the lesion. BBB opening, however, has not been shown without damage, and the mechanisms by which HIFU induces BBB disruption remain unknown. We show that HIFU is capable of reversible, nondestructive, BBB disruption in a targeted region-of-interest (ROI) (29 of 55 applications; 26 of 55 applications showed no effect); this opening reverses after 72 h. Light microscopy demonstrates that HIFU either entirely preserves brain architecture while opening the BBB (18 of 29 applications), or generates tissue damage in a small volume within the region of BBB opening (11 of 29 applications). Electron microscopy supports these observations and suggests that HIFU disrupts the BBB by opening capillary endothelial cell tight junctions, an isolated ultrastructural effect that is different from the mechanisms through which other (untargeted) modalities, such as hyperosmotic solutions, hyperthermia and percussive injury disrupt the BBB.