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Background: Herpes simplex virus encephalitis (HSVE) is the most morbid clinical syndrome associated with the human herpes virus. Despite treatment with appropriate dosages of acyclovir, neurologic relapse of HSV infection have been reported after cranial surgery. Rarely, neurological deterioration due to postinfectious inflammatory response without demonstrable HSV reactivation may recur following cranial surgery. Case Description: We report a case of a 17-year-old girl who presented with a HSVE relapse on the 6 th postoperative day following resective surgery for medically refractory epilepsy and review the literature. Postinfectious inflammatory reaction may be the underlying mechanism in cases with no HSV identified on cerebrospinal fluid (CSF) or brain polymerase chain reaction (PCR), such as in the current case. Conclusion: HSVE must be suspected in patients with previous history of HSVE and postoperative fever associated with an altered state of consciousness and/or seizures. Considering the high mortality and morbidity rates associated with HSVE, an adequate prophylactic administration of acyclovir should be considered for patients with previous history of HSVE undergoing neurosurgical procedures, especially when surgery involves the site of a previous herpetic lesion.