Inclusion Criteria:

• Age 18 years or older
• HSV-2 seropositive by Western blot OR documented culture positive for HSV-2 from anogenital site
• 2 or more vaginal or anal sex partners in the past 12 months
• Not currently in a monogamous sexual relationship of >= 6 months duration
• Willing and able to be randomized and comply with the study protocol

Exclusion Criteria:

• Pregnancy or intention to become pregnant within the next year
• Suppressive therapy with acyclovir, valacyclovir, or famciclovir within 2 weeks of enrollment/randomization
• 6 or more symptomatic herpes recurrences in the prior 12 months or in the 12 months prior to starting suppressive therapy if on suppressive therapy during the prior 12 months
• HIV seropositive or known immunocompromising medical condition. HIV negative test must be performed within 60 days of Visit 1 (enrollment/randomization). For current or former participants in HIV vaccine clinical trials for whom HIV vaccine-induced seropositivity potentially leading to vaccine study unblinding may be a concern, a report from the Seattle HVTU documenting that the participant is HIV uninfected based on HIV testing done within 60 days of Visit 1 will be accepted in lieu of HIV testing done at our clinic.
• Intention to move from the Seattle area within the next year
• Known allergy, intolerance, or medical contraindication to acyclovir
• Inability to understand, speak, and read English