11 of 24 immunocompromised patients with mucocutaneous herpes simplex virus (HSV) infections were given intravenous acyclovir in a randomised double-blind placebo-controlled study. Patients receiving acyclovir experienced no major adverse effects. The median times to cessation of new lesion formation, lesion crusting, lesion healing, cessation of pain, and termination of viral shedding were shorter in the acyclovir-treated group than in the placebo group. The time-to-event probability curves for the acyclovir and placebo groups were significantly different for cessation of pain (p = 0.032) and termination of viral shedding (p = 0.004). The median times to termination of viral shedding were also statistically different (p = 0.045). Acyclovir seems to be a non-toxic and effective treatment for mucocutaneous HSV infections in immunocompromised patients.