To identify clinical signs of disease that might lead to more rapid recognition in treatment, we reviewed the time from onset of illness to diagnosis of 42 consecutive cases of neonatal herpes simplex virus (HSV) infection seen between 1965 and 1984. The first signs of illness included mucocutaneous lesions in 14, central nervous system signs in 20, fever in 6 and respiratory insufficiency in 2 infants. The median time from onset of illness to presentation to medical personnel was 1 day. The median time from presentation to medical personnel to obtaining viral cultures was 3 days (range, 1 to 11) and was similar in infants who did and did not have mucocutaneous lesions. Viral cultures were performed within 24 hours of admission on 8 of 13 noncongenitally infected infants born between 1982 and 1984 compared to 5 of 24 seen between 1965 and 1981 (P less than 0.03). However, a greater than 72-hour delay between presentation to medical personnel and obtaining viral diagnostic studies occurred in 33, 40 and 14% of infants born in the years 1965 to 1977, 1978 to 1981 and 1982 to 1984. Involvement of additional organ systems by HSV was noted in 57% of infants between the time from presentation to medical personnel and diagnosis. Neonatal HSV infection was often severe by the time patients presented to medical personnel, and the disease usually progressed rapidly. To achieve a better therapeutic outcome for infants with neonatal herpes, consideration should be given to the initiation of antiviral therapy on presumptive clinical and epidemiologic grounds. Future strategies for therapy of neonatal herpes should be directed at preventing the acquisition of disease.