The purpose of this study is to test whether long-term treatment with oral acyclovir improves the outcome for infants with herpes simplex virus (HSV) disease of the skin, eyes, and mouth (SEM disease). Study participants will include infants in the US and Canada who have HSV disease of the skin, eyes, and mouth, with no central nervous system disease present. Initially, all subjects will be treated with acyclovir administered through IV access (through the vein) for 14 days while hospitalized. Participants will then be placed in one of two groups, acyclovir given by mouth or a placebo (substance with no medication present). The participant and the study site will not know to which group the subject is assigned. All children will be followed at 6, 12, 24, 36, 48, and 60 months of age. During the follow up visits, physicals, hearing assessments, eye assessments, and neurological assessments will be completed.

HSV complicates 1 out of every 3,000 births in the United States. This study focuses on infants with HSV infection isolated to the skin, eyes and mouth (SEM disease). Medication (acyclovir) given through a vein (IV) helps to treat SEM lesions. However, in about half the babies with SEM disease, HSV will come back after IV acyclovir treatment is stopped. HSV may come back in the central nervous system, the SEM or other body organs, causing serious complications. Long-term (6 months) treatment with oral acyclovir following IV acyclovir may reduce the reappearance of HSV disease. In this study, infants initially receive the standard treatment for SEM disease: IV acyclovir for 14 days. Eligible patients are randomized to receive a syrup that contains either acyclovir or placebo (contains no medicine) by mouth for 6 months. Patients are followed for any recurrences of HSV lesions and will receive medical treatment for such lesions. Patients will return to the clinic for follow-up evaluations once a year for 5 years after study treatment is completed.

Inclusion Criteria:

1. Isolation by viral culture of HSV-1 or HSV-2 from cutaneous lesions, conjunctivae, or oropharynx. Detection of HSV at any of these sites is sufficient, and the presence of skin lesions is not required for study enrollment.
2. Normal CSF indices (<22WBCs/mm(to the 3rd) and protein <115 mg/dl for term infants; (<25WBCs/mm(to the 3rd) and protein <220 mg/dl for preterm infants both at the time of diagnosis of HSV disease and at the time of study randomization.
3. No evidence of HSV CNS disease by CT with contrast, MRI with gadolinium, or head ultrasound (HUS) [NOTE: CT with contrast is the preferred imaging study].
4. Normal EEG, if performed [NOTE: EEG is suggested for the evaluation of infants with HSV disease but is not required for this study].
5. No evidence of visceral dissemination of HSV infection (normal liver function tests, normal CXR, etc.).
6. Negative CSF HSV PCR results from specimens obtained both within 72 hours of initiation of intravenous acyclovir therapy and within 48 hours prior to completion of intravenous acyclovir therapy.
7. </equal to 28 days of age at the time of initial presentation with SEM disease.
8. Birth weight >/equal to 800 grams.

Exclusion Criteria:

1. Infants with either grade 3 or grade 4 intraventricular hemorrhage (IVH) prior to study enrollment.
2. Breast feeding infants whose mothers are taking acyclovir, valacyclovir, or famciclovir for >120 hours (>5 days). If at any point following enrollment the mother takes these antiviral drugs for >120 hours (>5 days), she will be asked to refrain from breast feeding while taking the drug.
3. Infants known to be born to women who are HIV positive (but HIV testing is not required for study entry). These infants are at known risk for acquiring HIV, which would alter their immune response to other infections, including HSV infection. Additionally, they may be receiving antiretroviral and/or antiviral drugs during the time in which the study of suppressive oral acyclovir is being conducted. As such, they will be excluded if the mother's positive HIV status is known at the time of evaluation for study inclusion. If at any point following enrollment it is learned that an infant is HIV positive, he/she will be continued on the study protocol.
4. Infants with either CNS or disseminated HSV infection. Patients with CNS HSV infection will be considered for enrollment and randomization in the ongoing CASG evaluation of oral suppressive acyclovir therapy following neonatal HSV infections involving the CNS.
5. Infants with creatinine >1.5mg/dl at time of study enrollment.
6. Infants receiving acyclovir expectantly do not qualify for this study because they never developed HSV disease. Expectant therapy describes infants who are cultured at ~24 hours of life because of a risk of HSV infection (i.e. they are born to women with active genital lesions). Oftentimes, if these cultures are positive, the infant will receive a course of intravenous acyclovir to prevent the development of HSV disease. However, since they never actually had HSV disease, their potential outcome cannot be compared with infants with typical SEM disease, and so they are not included in this study.