Eighty-five immunocompromised patients were entered into a randomized, controlled, crossover study of mucocutaneous herpes simplex virus (HSV) infections. Thirty-nine patients (group A) received vidarabine for seven days followed by placebo for an additional seven days. Forty-six patients (group B) received the reverse regimens. Therapy did not significantly accelerate healing for the total population as assessed by loss of virus from lesions, cessation of lesion formation, and time to crusting. Group A patients demonstrated accelerated loss of pain from lesions (P = 0.0099) and defervescence (P = 0.03). Patients in group A who had HSV type 1 (HSV-1) infections or who were over 40 years of age did clear virus from lesions more rapidly (P = 0.04 and P = 0.03, respectively). No toxicity or significant adverse effects could be attributed to vidarabine administration. Benefit from vidarabine therapy is limited to immunocompromised patients over 40 years of age with HSV-1 infections.