Background: The BBB prevents the passage of most drugs from the blood to the brain and may be responsible for the limited efficacy of current chemotherapies in GBM patients. Two to four minutes of LIPU in combination with injection of micron-sized microbubbles has been shown to be a safe method for disrupting the BBB for a duration of 6 hours to increase the passage of drugs such as carboplatin by 5 to 7 fold in normal brain. Methods: Patients with recurrent GBM were implanted with a 1 MHz, 10-mm diameter pulsed ultrasound device in a burr hole during additional debulking surgery or during a dedicated procedure under local anesthesia. Ultrasound dose was escalated using a 3+3 Simon design. The device was activated monthly in combination with injection of a sulfur hexafluoride microbubble to transiently disrupt the BBB in 5 cm³ of the tumor field before IV administration of carboplatin chemotherapy (AUC4-6). Patients received 150-270 seconds of pulsed ultrasound < 1 hour prior to chemotherapy. BBB disruption was visualized using contrast-enhanced T1w MRI, and patients were monitored clinically and with T2, FLAIR, DWI and SWI sequences. Tumor progression was evaluated using the RANO criteria. Results: Nineteen patients were treated by LIPU until tumor progression. In 65 ultrasound sessions, 52 showed BBB disruption. The median number of monthly sonications per patient was 3 and ranged from 1-10. No significant adverse events related to ultrasound sonications were observed. Six patients (31%) had long PFS (19, 20, 35, 38, 40, 52 weeks). When tumor recurrence occurred, it was predominantly outside of the ultrasound sonication field. Conclusions: This trial has demonstrated that LIPU is a safe modality for disrupting the BBB in GBM patients and may increase the effectiveness of drug therapies in the brain. The sonication of larger volumes of brain may further increase the effectiveness of this therapy in patients with GBM. Clinical trial information: NCT02253212