Neurotoxicity of acyclovir is an often reported side effect, especially in critically ill patients with renal failure, but this diagnosis is often overlooked due to overlapping pathological symptoms. To illustrate this we present a 69-year-old woman on immunosuppressive therapy for a kidney transplant with a deteriorating clinical course of Epstein Barr virus encephalitis who was transferred to the intensive care unit and died after developing acute renal failure during treatment with high dose (10 mg/kg tid) intravenous acyclovir. Acyclovir serum concentrations were measured (trough 2.9 - 5.1 mg/L) indicating that at least part of the patient's encephalopathy may have been the result of acyclovir neurotoxicity, thus complicating the clinical decision making on the intensive care unit. Although no threshold for acyclovir trough concentrations has been established to assess the risk of neurotoxicity, the contribution of this adverse effect to the neurological findings in our patient cannot be excluded. Further efforts to investigate the relationship between acyclovir exposure and neurotoxicity are warranted. Copyright © 2009, Nederlandse Vereniging voor Intensive Care. All Rights Reserved.