We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex. (N Engl J Med 297:289–294, 1977) Encephalitis due to herpes simplex virus is considered the most common cause of sporadic fatal encephalitis in this country.1,2 Both the high mortality and the attendant morbidity in the few survivors345 have prompted attempts at therapy with experimental compounds. These included the pyrimidine nucleoside analogs, 5-iodo-2′-deoxyuridine (IDU, idoxuridine) and 1-β-D-arabinofuranosyl cytosine (ara-C, cytosine arabinoside), which inhibit cellular as well as viral DNA replication in vitro.678 Because of the clinical need and despite a paucity of animal model studies, these two agents were used in uncontrolled trials with reports of benefit.9101112131415 Idoxuridine appeared to be gaining acceptance until controlled studies demonstrated. © 1977, Massachusetts Medical Society. All rights reserved.