Methods: We plan an individually randomized double blind placebo-control trial of the WHO and US CDC recommended dose of 3-times daily acyclovir for a 5-day treatment course. The trial will be conducted at two primary health care clinics in Johannesburg, South Africa. A total of 600 men presenting to the clinic with GUD will be enrolled in the study. Consenting participants will be randomized to receive either acyclovir plus syndromic management or placebo plus syndromic management. Syndromic management for genital ulcer disease will consist of one dose antibiotics to cover for syphilis and chancroid. Participants will be followed for a month; during follow-up visits duration of ulcers, ulcer number and size will be evaluated and ulcer, blood and semen samples collected to test for HIV RNA viral loads among HIV-positives and for HSV-2 shedding.