Oral acyclovir was given prophylactically to 37 children in the early stages of three outbreaks of herpes simplex virus type 1 (HSV-1) infection and the results were compared with those in untreated control subjects in two other outbreaks. The rates of seroconversion to HSV were significantly reduced in children treated with acyclovir compared with control subjects (91% vs 27%, P less than .001). The incidence of symptomatic disease was also significantly reduced (82% vs 0%, P less than .001). In some children receiving prophylactic acyclovir, anti-HSV antibody titers did not rise despite the presence of replicative HSV on throat swabs just before the start of treatment. Restriction endonuclease analysis of isolated HSV-DNA confirmed that one strain was responsible for the five outbreaks. No resistance to acyclovir was detected during the study, and no adverse effects of treatment were noted. In conclusion, short-term prophylactic acyclovir may limit the spread and reduce clinical manifestations of HSV infections in closed communities, although this use should be restricted to communities where severe symptoms are observed.