Twelve children ages 1 to 5 years and one adult with hand-foot-and-mouth disease were treated with oral acyclovir within one to two days of onset of the rash. Symptomatic relief, defervescence, and significant involution of lesions were seen within twenty-four hours of initiating therapy. Acyclovir was continued for five days, by which time palmar, plantar, and oral lesions were virtually gone. Acyclovir is a molecule tailored to inactivate the thymidine kinase of the herpesvirus. Since the Coxsackie A16 virus causing hand-foot-and-mouth disease lacks this enzyme, the beneficial therapeutic effect must be explained on other grounds, possibly due to enhancement of the antiviral effect of the patient's own interferon.