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Clinical researches indicate that acyclovir can be used to herpes simplex encephalitis (HSE). However, no systematic review has explored its efficacy for the treatment of HSE. Therefore, this study systematically will investigate the efficacy and safety of acyclovir for patients with HSE.We will search the following databases from inceptions to March 1, 2019 without any language restrictions: Cochrane Library, Embase, MEDICINE, PsycINFO, Web of Science, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. This study will include randomized controlled trials that assess the efficacy and safety of acyclovir for patients with HSE. Two authors will independently carry out the study selection, data extraction, and risk of bias assessment. Cochrane risk of bias tool will be used to assess the risk of bias assessment.This study will systematically assess the efficacy and safety of acyclovir for HSE. The primary outcome is mortality rate, which is measured by Glasgow coma score, or other instruments. The secondary outcomes include quality of life, as assessed by 36-Item Short Form Health Survey or relevant scales; overall survival, the number of patient who died; the number of patient who had severe sequelae, and adverse events.The findings of this study may provide the existing evidence on the efficacy and safety of acyclovir for HSE.PROSPERO CRD42019125999.