Herpes simplex encephalitis and neonatal herpes simplex virus infections are important consequences of herpes simplex virus infections of humans. The association of both diseases with significant mortality and morbidity has prompted intensive therapeutic trials designed to improve outcome. The NIAID Collaborative Antiviral Study Group has been able to demonstrate that vidarabine therapy decreases the mortality and improves morbidity for both herpes simplex encephalitis and neonatal herpes simplex virus infections. Nevertheless, mortality for both diseases is about 40% and many survivors are left with significant neurological impairment. With the hope of improving outcome, we initiated comparative trials of vidarabine and acyclovir for these two diseases. This report summarizes the status of these trials, which are still underway, with particular reference to the complexities of studies such as these. Because adequate numbers of patients for definitive statistical analyses have not been entered into the trial, data were assessed according to outcome for the entire group, irrespective of drug administered. The mortality of herpes simplex encephalitis and neonatal herpes simplex virus infections has been reduced to 34 and 30%, respectively, a decrease of approximately 10% for each disease. Further analyses await completion of the trials.