Acyclovir(ACV)-resistant herpes simplex virus type 2 (HSV–2) was isolated from apatient with acquired immunodeficiency syndrome after long-term but intermittent ACV therapy. These thymidine kinase-defective isolates were sensitive in vitro to foscamet. While combined therapy with ACV and interferon produced only partial clinical improvement, the in vitro effect of this combination against an ACV-resistant isolate from the patient was strongly synergistic. Ashort course (10–12 days) of intravenous foscamet controlled severe ulceration, and clinical improvement lasted 6 months. After recurrence and further courses of foscamet, however, the patient responded poorly, and subsequent HSV isolates were resistant to both ACV and foscamet and hypersensitive to aphidicolin.