A previously healthy 7-year-old girl suffered from oral herpetic gingivostomatitis. After four days, oral administration of acyclovir (ACV), 1,000 mg in five divided doses, was started. She became irritable and intermittently delirious next day. Laboratory tests of blood and cerebrospinal fluid (CSF) were within normal limits and EEG showed no abnormality. Brain CT and MRI demonstrated mild asymmetry of the lateral ventricle. SPECT showed low perfusion area in the bilateral thalamus. The titer of IgG and IgM against herpes simplex virus (HSV) was increased in the serum but not in the CSF. A PCR study of HSV DNA was negative in the CSF. ACV was discontinued after 5 days' administration and she recovered from neurological disorders within 48 hours. ACV neurotoxicity is self-limiting and dose-dependent. It may be distinguished from herpes simplex encephalitis by the lack of fever, headache, focal neurologic signs, and abnormal CSF and neuroradiological findings. However, when the differentiation should be difficult, we believe that the administration of ACV can be carefully continued because the potential fatality of HSE is high while ACV neurotoxicity is reversible.