Sequential isolates of herpes simplex virus type 1 (HSV-1) from a child with severe combined immunodeficiency were examined for sensitivity to acyclovir. Early intravenous courses of acyclovir resulted in dramatic clinical improvement and were associated with the isolation of sensitive strains of HSV-1 (ID50[dose inhibiting 50% of control plaques], 0.010-0.106 microgram/ml), whereas later recurrences following intravenous, oral, and ophthalmic therapy were characterized by low-grade chronic lesions (ID50, 1.04-9.43 microgram/ml) that were unresponsive to acyclovir despite serum levels of up to 10.45 microgram/ml. Diminished sensitivity was associated with reduced viral thymidine kinase activity, and linked resistance with idoxuridine was detected in the isolates from the patient's eye. Intracerebral and cutaneous snout inoculation of a resistant isolate into BALB/c, hairless, and athymic nude mice revealed a 100- to 1,000-fold decrease in virulence as compared with an early sensitive isolate. Acyclovir-resistant HSV-1 can emerge in certain clinical settings but may be associated with diminished virulence.