OBJECTIVE: By a randomised, double-blind, placebo-controlled trial of aciclovir 800 mg twice daily for 5 days added to the syndromic management of genital ulcer disease (GUD) to determine the impact on ulcer healing and HIV outcomes. METHODS: Patients presenting with GUD in Malawi were evaluated for HIV and herpes simplex virus type-2 (HSV-2) serologies, ulcer aetiology, lesional, genital and plasma HIV-1 RNA and CD4+ count. Patients were followed up at days 2, 4, 7, 14 and 28. The primary study outcome was ulcer healing at day 14, with secondary outcomes being lesional and genital HIV-1 shedding at day 14 and HIV-1 plasma viral load at day 28 among HIV-1/HSV-2 co-infected individuals. RESULTS: Four hundred and twenty-two patients (74% male) were randomised (208 to aciclovir, 214 to placebo), of whom 61% were HIV-1 seropositive and 72% HSV-2 seropositive; 67% (267/398) had HSV-2 ulcers. 85% of ulcers were healed at day 14 with no difference between treatment arms (risk ratio (RR)=1.02, 95% CI 0.93 to 1.11). Among 244 HIV-1/HSV-2 co-infected individuals, aciclovir reduced lesional HIV-1 RNA (adjusted RR=0.64, 95% CI 0.41 to 0.99) and seminal HIV-1 RNA (adjusted RR=0.59, 95% CI 0.40 to 0.88), but not cervical HIV-1 RNA or plasma HIV-1 RNA. CONCLUSIONS: Episodic HSV treatment with aciclovir added to syndromic management did not produce a significant clinical benefit in this African population.