Intrathecal administration of antibiotics can be accomplished either by intralumbar or intraventricular route allowing a high and/or prolonged antibiotic concentration in the cerebrospinal fluid (CSF). Increase of ventriculitis rates associated to CNS shunts that involve multiresistant microorganisms has made relevant this route of administration due to the limited penetration of antibiotics active against multiresistant organisms through the blood brain barrier. Aminoglycosides and vancomycin are the most common antibiotics used for this purpose. In order to accomplish bactericidal activity and due to its concentration-dependent mechanism, aminoglycosides should reach concentrations 8 to 10 times above the MIC of a given Gram negative bacilli. Doses of 2 to 5 mg for gentamicin and 30 mg for amikacin every 24 h allow this purpose and has been associated to clinical cure in several reports. Vancomycin attains its bactericidal activity by a time-dependent mechanism and the best predictor of clinical efficacy is the time area under the curve (AUC) above the MIC. Doses of 20 mg every day assure an adequate temporal exposition to the drug if trough concentrations of 5 to 10 µg/ml are obtained, and have been related to clinical efficacy. Intrathecal concentrations for these antibiotics are higher and therapeutically effective when they are administered through intraventricular route than by intralumbar puncture. Intraventricular antibiotics are indicated when a patient affected by ventriculitis does not improve despite maximal-doses systemic antibiotic therapy and/or CSF remains positive for microorganisms. In order to secure efficacy, intraventricular antibiotics should be implemented with removal of the ventricular drain associated to infection. Experience with quinuspristin/dalfopristin or linezolid for the treatment of staphylococcal ventriculitis is yet scarce.