Objective: The purpose of this study was to estimate the efficacy of valacyclovir suppressive therapy in pregnant women with recurrent genital herpes. Study design: At 36 weeks' gestation, herpes simplex virus (HSV)-2 seropositive women were randomized to receive oral valacyclovir 500 mg or placebo twice daily until delivery. Genital tract and neonatal specimens were collected weekly for HSV culture and qualitative polymerase chain reaction (PCR) assay to detect viral DNA from the time of randomization to delivery. Both maternal and neonatal toxicity measures were obtained. Results: The 112 enrolled women (57 valacyclovir, 55 placebo) had similar HSV recurrence risks, including mean number of active HSV recurrences before randomization during the index pregnancy (1.1 ± 1.9 vs 1.5 ± 2.1, P = .308) and days between randomization and delivery (20.3 ± 10.2 vs 22.0 ± 8.9, P = .344). The number of women with clinical HSV recurrences between the time of randomization and delivery was significantly lower in the valacyclovir versus placebo group (10.5% vs 27.3%; P = .023, RR 0.4, 95% CI 0.2-0.9). Shedding of HSV within 7 days of delivery was similar in the valacyclovir and placebo group (10.4% vs 12.0%, P = .804; RR 0.9, 95% CI 0.3-2.7), as was the number of women with clinical HSV lesions at delivery (5.3% vs 14.6%, P = .121; RR 0.4, 95% CI 0.1-1.3). No neonates had symptomatic congenital HSV infection before discharge or up to 2 weeks' postpartum, and no clinical or laboratory safety concerns were identified. Conclusion: Administration of valacyclovir beginning at 36 weeks' gestation to women with a history of recurrent genital HSV reduced the number of women with subsequent clinical HSV recurrences. © 2006 Mosby, Inc. All rights reserved.