Background: The BBB limits the efficacy of many chemotherapies in GBM patients by blocking the passage of drugs to the brain. Two to four minutes of LIPU in combination with injection of micron-sized microbubbles can transiently disrupt the BBB to increase the passage of drugs such as carboplatin. Methods: This first-in-man, single arm, monocentric trial was performed at Hôpital Universitaire Pitié-Salpêtrière, Paris, France from 2014-2018. Recurrent GBM patients were implanted with (1) or (3) 1 MHz, 10-mm diameter cranial devices in burr holes during debulking surgery or during a dedicated procedure under local anesthesia. Ultrasound dose was escalated using a Simon titration design. The device was activated monthly to transiently disrupt the BBB before IV administration of carboplatin (AUC4-6). BBB disruption was visualized using MRI and patients were monitored clinically. Results: Twenty-seven patients were implanted with LIPU devices and 25 per-protocol were sonicated: 19 patients with (1) US emitter and six patients with (3) US emitters. In 85 ultrasound sessions, BBB disruption was visible on post-sonication T1w MRI for 72 sonications and was ultrasound dose dependent. Few transient and manageable severe related adverse events were observed: a partial seizure, two cases of transient edema (H1 and D15) and one transient facial palsy. No carboplatin-related neurotoxicity was observed. All patients treated with (1) emitter had tumor progression and 3/19 patients were alive. In this cohort, patients with no or poor BBB disruption (n = 8) had a median PFS of 13 weeks, and a median OS of 8.9 months. Patients with clear BBB disruption (n = 11) had a median PFS of 15 weeks, and a median OS of 13 months. Conclusions: LIPU was well tolerated and may increase the effectiveness of drug therapies in the brain. The sonication of larger volumes of brain in recurrent GBM will be investigated in a future trial and may further enhance the observed effectiveness of this treatment modality. Clinical trial information: NCT02253212. Clinical trial information: NCT02253212