<p>The purpose of the study is to analyze the clinical features, treatment, and survival outcomes of Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) with positive&#xa0;cerebrospinal fluid (CSF) EBV-DNA in children. Patients diagnosed with EBV-HLH admitted to our center from January 2019 to August 2024 were enrolled and divided into a CSF-EBV group and a non-CSF-EBV group based on CSF EBV-DNA test results. Neurological manifestations were observed in only 33.3% (13/39) of children with CSF-EBV positivity, while 48.7% (19/39) showed abnormal brain magnetic resonance imaging findings. The CSF-EBV group had a higher blood EBV-DNA load (<i>P</i> = 0.002) and a lower CD4⁺/CD8⁺ ratio (<i>P</i> = 0.034) compared with the non-CSF-EBV group. A strong positive correlation was observed between CSF EBV-DNA load and CSF cell count (<i>r</i> = 0.800, <i>P</i> &lt; 0.0001). Overall survival was shorter in the CSF-EBV group (<i>P</i> = 0.017). Multivariate Cox regression identified EBV-associated central nervous system (EBV-CNS) infection as a potential&#xa0;independent risk factor for poor prognosis (<i>HR</i> = 6.077, 95% <i>CI</i>: 1.345–27.435, <i>P</i> = 0.019). Intrathecal methotrexate and dexamethasone effectively reduced CSF viral load (<i>P</i> = 0.003) and cell count (<i>P</i> = 0.042), but did not significantly improve overall survival (<i>P</i> = 0.3). </p><p> <i>Conclusion</i>: EBV-CNS infection&#xa0;may be&#xa0;an independent risk factor for poor prognosis in pediatric EBV-HLH, underscoring the importance of CSF EBV-DNA testing, particularly in patients with high blood loads. Although intrathecal therapy effectively reduced CNS viral load and inflammation,&#xa0;its survival benefit requires further validation in large-scale prospective studies.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry nameend="c2" namest="c1"> <p><b>What is Known:</b></p> <p>• <i>CNS involvement is a well-established poor prognostic factor in HLH</i>.</p> <p>• <i>EBV-CNS infection is an independent prognostic risk factor in adult EBV-HLH</i>.</p> </entry> </row> <row> <entry nameend="c2" namest="c1"> <p><b>What is New:</b></p> <p>• <i>EBV-CNS infection is an independent prognostic risk factor in pediatric EBV-HLH</i>.</p> <p>•<i>While intrathecal therapy effectively reduces CSF viral load and inflammation, its survival benefit still requires further validation through large-scale prospective studies</i></p> </entry> </row> </tbody> </tgroup> </Table></p>