SignificanceThe blood–brain barrier (BBB) is a critical obstacle to delivering most therapeutics into the brain. In this study, we report combined MRI, histological, and real-time acoustic emissions monitoring findings from a Phase 0 clinical trial examining microbubble-enhanced transcranial focused ultrasound for controlled BBB opening in patients with infiltrating gliomas. The data revealed the capability of this technology to provide safe, controlled, and tightly monitored BBB opening through the intact skull. Our findings demonstrate the capability of this technology to tune BBB opening in real-time, creating opportunities for improved treatment of brain tumors.