OBJECTIVE Shunt infection causes death in many patients diagnosed with hydrocephalus and increases the duration of hospitalization and treatment costs. A high percentage of children are forced to undergo re-surgery due to shunt dysfunction or infection. The present study aimed to investigate the role of intraventricular (IVT) vancomycin in the prevention of ventricular shunt infection in children with hydrocephalus who were referred to Akbar Hospital in Mashhad, Iran, between the years 2017 and 2021. METHODS The present descriptive cross-sectional study was conducted on 192 children with hydrocephalus who underwent shunt surgery at Akbar Hospital in Mashhad, Iran, between the years 2017 and 2021. Patients were divided into two groups of intervention (n=69) and control (n=123). The patients in the intervention group received 30 mg of IVT vancomycin during shunt surgery. The rate of shunt obstruction and infection were then compared between the two study groups. RESULTS The two study groups were matched in terms of demographic and clinical information except for gender (P=0.02). Moreover, no significant difference was reported between the two groups in terms of intelligence development (χ2=0.51; P=0.47), verbal development (χ2=0.1; P=0.75), and movement development (χ2=1.05; P=0.3). The frequency of shunt infection and shunt obstruction was estimated at 8.8% and 18.2%, respectively. The shunt infection rate was lower in the vancomycin IVT group than in the control group (χ2=4.07; P=0.04), while no difference was observed between the two groups in terms of shunt obstruction (χ2=3.66; P=0.056). The comparison of the two study groups indicated no significant difference between them in terms of mortality (χ2=0.004; P=0.95). CONCLUSIONS It seems that IVT vancomycin should be recommended for inclusion in hydrocephalus surgery protocol to reduce postoperative shunt infection. It is recommended that shunt protocols be adopted in future multicenter prospective randomized controlled trials on the reduction of ventriculoperitoneal shunt infections to further evaluate the efficacy of IVT antibiotics.