Central nervous system infection of Herpes simplex virus (HSV) is the most common etiologic agent of the non-epidemic fatal form of encephalitis. Relapse of HSV encephalitis is rare in childhood. In this report, we present our experience in a 36-month-old child with relapse of HSV encephalitis after 14-day acyclovir therapy. A 36-month-old boy who was presented with deterioration in speech and motor functions and fluctuation of consciousness was treated with acyclovir for 14 days for HSV encephalitis. He was discharged since his cerebrospinal fluid findings returned to normal range and clinical improvement was seen. Ten days later, he was readmitted to our clinic with acute fever, focal convulsions and choreoathetoid movements, and altered consciousness. Acyclovir was started immediately, but he died on the 17th day because of respiratory failure. Relapses due to HSV encephalitis are rare and limited to a small number of case reports in the literature. Persistence of HSV, detection of high viral load or detection of HSV by polymerase chain reaction, prior corticosteroid therapy, low total dosage of acyclovir (especially for children under 2 years of age) and short duration of therapy were suspected risk factors. Even absence of pleocytosis and normal cerebrospinal fluid biochemistry in our patient after treatment did not indicate eradication of HSV. In our opinion, treatment duration of HSV encephalitis, especially in small children, must be at least 21 days. Clinical and experimental studies are required since only case reports on this topic exist.