Abstract Background: Intravenous antibiotic administration is an essential component in the management of patients with cerebrospinal fluid (CSF) infections. However, very low concentrations reach the CSF because of the blood-brain barrier. Local irrigation with antibiotics could be a promising option to enhance the outcomes for such patients. Aim of Study: In this prospective randomized trial, we evaluated whether ventricular irrigation with local antibiotics had a significant benefit in these cases. Patients and Methods: Fifty patients diagnosed with CSF infections were divided into two groups; Group I included 25 patients who had CSF irrigation with local antibiotics, and Group II included the remaining patients who had external ventricular drainage (EVD) only. The main outcomes were the modified Rankin scale (MRS), the hospitalization period, and mortality. Results: Preintervention demographic, clinical, and labo-ratory criteria were statistically comparable between the two groups. However, patients in the irrigation group showed earlier improvement in their blood leucocytes (41 vs. 71 days), CSF leukocytes (4 vs. 12 days), and CSF proteins (12.9 vs. 27.22 days) compared to the other group. There was a signif-icant shortening in the duration of EVD placement in the irrigation group (18 vs. 60 days in the other group). Moreover, patients in the irrigation group had a lower disability scale. Twelve patients died in the non-irrigation group (48%), which was significantly higher than the mortality rate in the irrigation group (20%). Conclusion: CSF irrigation with local antibiotics is asso-ciated with significantly better outcomes in patients with CSF infections.