BACKGROUND Postneurosurgical ventriculitis is mainly caused by coagulase-negative staphylococci. The rate of linezolid-resistant Staphylococcus epidermidis (LRSE) is increasing worldwide. OBJECTIVE To report clinical, epidemiological and microbiological data from a series of ventriculitis cases caused by LRSE in a Spanish hospital between 2013 and 2016. METHODS Cases of LRSE ventriculitis were reviewed retrospectively in a Spanish hospital over a four-year period. Clinical/epidemiological data of the infected patients were reviewed, the isolates involved were typed by pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing, and the molecular bases of linezolid resistance were determined. RESULTS Five cases of LRSE ventriculitis were detected. The patients suffered from cerebral haemorrhage or head trauma that required the placement of an external ventricular drain; spent a relatively long time in the intensive care unit (ICU) (10-26 days); and three out of the five patients had previously been treated with linezolid. All LRSE had the same PFGE pattern, belonged to ST2, and shared an identical mechanism of linezolid resistance. Specifically, all had the G2576T mutation in the V domain of each of the six copies of the 23S rRNA gene, together with the Q136L and M156T mutations and the 71GGR72 insertion in the L3 and L4 ribosomal proteins, respectively. CONCLUSIONS The high ratio of linezolid consumption in the ICU (7.72-8.10 defined daily dose/100 patient-days) could have selected this resistant clone, which has probably become endemic in the ICU where it could have colonized admitted patients. Infection control and antimicrobial stewardship interventions are essential to prevent the dissemination of this difficult-to-treat pathogen, and to preserve the therapeutic efficacy of linezolid.