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It is uncertain whether episodic acyclovir will enhance ulcer healing if delivered at primary health care settings, because there is often a delay in treatment initiation.A double-blind, randomized, placebo-controlled trial of 5-day acyclovir (400 mg 3 times daily) was conducted among men with genital ulcers in South Africa. Participants received syndromic management; were tested for ulcer etiology, human immunodeficiency virus (HIV), syphilis, and herpes simplex virus type 2 (HSV-2); and were seen over the course of a month to evaluate ulcer healing and HIV-1 RNA shedding. Outcomes were ulcer duration and HIV-1 RNA shedding, assessed on day 7 among HIV-1-seropositive participants with a herpetic ulcer.A total of 309 men received acyclovir, and 306 received placebo; 63% were HIV-1 positive. There were 295 HIV-1-positive participants with a herpetic ulcer. Acyclovir improved ulcer healing—61% of those receiving acyclovir healed by day 7, compared with 42% of those receiving placebo (adjusted relative risk, 1.4 [95% confidence interval, 1.1-1.8]; P=.003). Acyclovir also improved healing by a median of 3 days (P=.002) and reduced HIV-1 ulcer shedding on day 7 (24% for acyclovir vs 37% for placebo; P=.05).Addition of acyclovir to syndromic management will improve healing of genital ulcers and may potentially reduce HIV transmission in combination with other interventions.ClinicalTrials.gov identifier: NCT00164424.