Acyclovir produces neurologic symptoms that resemble extension of viral infection into the central nervous system. We discuss our observations in the cases of two patients with acyclovir neurotoxicity and review the findings of all previous reports in the English language literature. Systemic disease, most commonly renal dysfunction, preceded all 30 reported cases of acyclovir neurotoxicity. The most common symptoms were mental status disorder and involuntary movements. Measurement of serum acyclovir levels substantiated the diagnosis in only a subset of patients. Although all patients recovered, hemodialysis hastened the rate of recovery.