Herpes simplex virus type 1 is a common cause of severe sporadic encephalitis. Treatment with acyclovir is highly effective in this disease. We report the case of a 27-year-old, immunocompetent woman with acyclovir-resistant herpes simplex encephalitis. Although she had not been treated before, herpes simplex virus type 1 DNA from the cerebrospinal fluid showed a non-synonymous mutation in the thymidine kinase gene, which is likely to have caused resistance to acyclovir. Herpes simplex encephalitis resolved after treatment with foscarnet. To our knowledge, this is the first report of acyclovir-resistant herpes simplex virus encephalitis in an immunocompetent, previously therapy-naive adult.