A 28-year-old man with Wiskott-Aldrich syndrome presented with ulcerative-proliferative lesions on his face from which herpes simplex type 1 (HSV-1) was isolated. He was initially treated with 10 mg/kg of acyclovir (Zovirax) intravenously every 8 h, but his skin lesions worsened. Clinical resistance to acyclovir was suspected, and therapy with this drug was intensified. The dosage of acyclovir was increased to 45 mg/kg, administered by continuous infusion, and the lesions subsequently resolved. The strain of HSV recovered from the patient showed acyclovir-resistance in vitro, using the colorimetric method with neutral red. Herpes simplex virus resistance to acyclovir is rare. It is more common in immunocompromised patients if subtherapeutic doses are administered in the treatment of chronic persistent forms of infection. Whenever clinical resistance to acyclovir is suspected, the dosage should be increased to 2 mg/kg per h administered via an infusion pump. If no improvement is observed in the patient's condition with this regimen, a phosphorylated medication whose mechanism of action is not dependent on viral thymidine kinase, such as foscarnet (phosphonoformic acid), should be substituted.