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Abstract Importance Central nervous system infection is a severe illness in children. Little is known about the long‐term outcome in children with central nervous system infection of various etiologies. Objective The aims of this study were to investigate the long‐term outcomes of childhood acute central nervous system infection and to examine possible prognostic factors. Methods Of 172 children who were treated for acute central nervous system infection from January 2009 through December 2009, 139 were eligible for follow‐up evaluations. A structured interview was conducted with the parents 3.8–4.7 years after hospital discharge. The global outcome was determined in all patients using the Pediatric Version of the Glasgow Outcome Scale–Extended. Clinical features of the acute episode were retrieved from medical records. Results The outcome was favorable in 109 of 139 patients (78%), 38 (27%) were mildly impaired, six (4%) were moderately impaired, 14 (10%) were severely impaired and two (1%) were in a vegetative state. There were eight deaths. The most frequent symptoms were difficulty concentrating (16%), epilepsy (12%), limb paralysis (12%), memory impairment (10%), speech disorders (9%), irritability (9%). Significant risk factors for epilepsy included the presence of recurrent seizures or status epilepticus, the existence of pure spikes in the electroencephalogram, brain parenchyma abnormalities on neuroimaging and herpes simplex virus encephalitis (HSVE). A multivariate analysis identified three factors that were independently associated with poor outcome: coma, brain parenchyma abnormalities on neuroimaging and HSVE. Interpretation Most children with acute central nervous system infection experienced a favorable outcome 3.8–4.7 years after discharge from the hospital. Minor to severe disability persists in a high proportion of cases. Coma, brain parenchymal abnormalities on neuroimaging and HSVE may predict poor long‐term outcome.