A boy with Wiskott-Aldrich syndrome suffered from thymidine kinase (TK)-altered and aciclovir-resistant herpes simplex virus type 1 (HSV-1) skin infections. He presented with severe herpes simplex around the left eye in March 1993 at the age of 8 years. HSV-1 strain TAS was isolated and was shown to be susceptible to aciclovir (50% inhibitory concentration (IC50) 0.23 microg/mL). He was treated with intravenous (i.v.) high dose aciclovir, 2 mg/kg per h, which produced an improvement. About 1 year later (May 1994), a severe herpes simplex infection appeared on his face, arm, genitalia, back and foot. Treatment with i.v. aciclovir, 2 mg/kg per h, was initiated, but the skin lesions did not improve. HSV-1 strain TAR was isolated and was shown to be resistant to aciclovir (IC50 36 microg/mL). HSV-1 TAR and TAS were susceptible to vidarabine (IC50 4. 4 and 2.9 microg/mL, respectively). The skin lesions were treated with i.v. vidarabine, 15-20 mg/kg per day, and healed satisfactorily. However, in March 1995, the patient again experienced a severe herpes simplex infection around the left eye. HSV-1 strain R95 was isolated and was shown to be resistant to aciclovir (IC50 36 microg/mL). Diminished sensitivity of HSV-1 TAR and R95 to aciclovir was associated with reduced viral TK activity and loss of aciclovir phosphorylation activity.