Surgery close to or in contact with the ventricular system is challenging due to the complications. We sought to evaluate the effectiveness and safety of TachoSil® as a ventricular sealant in preventing complications after cranial surgery with an open ventricular system (OVS). This is a single-center and prospective cohort study We included patients who underwent elective surgery for supratentorial craniotomy and periventricular pathology between December 2020 and November 2023. We registered surgical complications arising from CSF dynamics (such as percutaneous cerebrospinal fluid (CSF) leakage, hydrocephalus, pseudomeningocele), infections, and other complications (postsurgical hematoma) adverse drug reactions (ADRs), reintervention or hospital readmission up to 90days after surgery. Forty interventions were performed on 39 patients, whose median age was 56years. Eleven patients (28.2%) had antecedents of previous surgery in the same location, 5 (12.8%) had previously received radiotherapy and chemotherapy, and 11 (28.2%) were smokers. Twenty-four patients (60%) underwent surgery for high-grade glioma, 8 (20%) for low-grade gliomas, 6 (15%) for metastasis and 2 (5%) for meningioma. Throughout the study and up to 90days after surgery, none of the patients presented an ADR. Only 2 patients (5%) presented with a surgery complications derived from ventricular opening (one patient with a percutaneous CSF leakage and one patients with external hydrocephalus). Both patients resolved with a ventriculoperitoneal shunt. TachoSil® is a dural sealant that can be used safely and effectively intraparenchymally in patients whose surgery involves a ventricular opening. Only 5% of treated patients presented complications arising from CSF hydrodynamics. No patients had pseudomeningocele, infections or complications related to the use of this sealant. To confirm these positive results, randomized and comparative clinical trials assessing the efficacy of TachoSil® in patients after cranial surgery with an OVS are essential. This study was registered in the Clinical Trials.gov (NCT05717335). Date May 1st, 2022.