INTRODUCTION: Herpes encephalitis is known to affect patients undergoing brain radiotherapy, but early diagnosis and treatment, the foremost determinants of disease outcome, remain challenging in this patient population. This can be due to attribution of symptoms to the brain tumor and radiation side effects, as well as patients' atypical clinical presentation. Here we sought to highlight pearls and pitfalls in the clinical course and diagnostic workup which may facilitate timely diagnosis and improve disease outcome. METHODS: Six patients with post radiation herpes encephalitis were identified in a retrospective review of Hadassah Medical Center medical records of between 2007 and 2022. Their clinical course, brain imaging, labs and EEG findings were included in the study. RESULTS: All six patients presented with fever and a confusional state and four had seizures. Lumbar puncture showed mild CSF pleocytosis in two of five patients, and PCR was positive for HSV1 in four out of five. MRI showed typical findings in all patients, though they were misinterpreted in two of six as disease exacerbation. EEG showed non convulsive status epilepticus in three patients. Outcome was favorable in half of patients. DISCUSSION: In patients undergoing radiotherapy to the brain and neck, fever and confusional state accompanied by new onset seizures, seizure exacerbation, changes in seizure lateralization and status epilepticus should lead one to consider a diagnosis of herpes encephalitis. A high index of suspicion, a timely workup and empiric treatment in this patient population can alter disease outcome.