OBJECTIVE: The goal was to describe herpes simplex virus (HSV) disease in neonates whose mothers received suppressive acyclovir therapy for HSV infection. STUDY DESIGN: A multicenter case series of 8 infants who developed neonatal HSV disease following maternal antiviral suppressive therapy during pregnancy. RESULTS: Eight infants were identified from New Jersey (5), Maine (1), New York (1), and Texas (1) between 2005 and 2009. All 6 mothers of infants infected with HSV who were screened prenatally for group B Streptococcus were positive; 1 mother was not tested and the other had bacterial vaginosis and genital human papillomavirus infection. Six mothers had a first clinical episode of genital HSV infection during this pregnancy; mothers with a prior history of genital HSV had no clinically recognized outbreak during the pregnancy. Perinatal transmission of HSV occurred in 7 infants (despite suppressive therapy until the day of delivery in 5 instances). Seven of 8 patients were born at term; 6 infants were male. In 7 of 8 cases, HSV was diagnosed by 8 days of age. Five infants had skin, eye, and mucous membrane disease, 2 had central nervous system disease (without and with disseminated disease), and one had intrauterine/disseminated disease. CONCLUSIONS: Although maternal antiviral suppressive therapy is an increasingly wide practice, physicians caring for neonates should be aware that suppressive therapy does not prevent neonatal HSV disease, which can have an atypical clinical presentation and drug resistance.