Herpes simplex encephalitis (HSE) is the most frequent cause of focal necrotizing encephalitis, accounting for approximately 2,500 cases annually in the United States. Studies initiated in the early 1970s have continuously evaluated promising antiviral drugs for the treatment of this disease, utilizing randomized, blinded, controlled clinical trial designs. Fundamental to the early studies was the requirement for brain biopsy in order to establish a diagnosis of HSE unequivocally by isolation of herpes simplex virus (HSV) from brain tissue in cell culture. From the outset of these studies in 1973, Data Monitoring Committees (DMCs) were established by the program sponsor, the National Institute of Allergy and Infectious Diseases (NIAID), to assess clinical trial performance, data quality, and outcome. With several iterations over a period of 30 years, these DMCs have terminated one trial because of excessive drug toxicity and two trials because of significantly reduced mortality in recipients of an active therapeutic. These studies represented the first clinical trials sponsored by NIAID that utilized a DMC. The role of the DMC in the monitoring of these trials is described. © 2006 Springer-Verlag New York.