Neurotoxicity associated with acyclovir use is infrequently encountered. However, the half-life of acyclovir is greatly prolonged in patients with end-stage renal disease, predisposing these patients to neurological side effects that are generally reversible but occasionally severe. In general, renal dialysis effectively decreases the serum level of acyclovir, which correlates with toxicity. We report an unusual case of delirium and coma in a patient undergoing hemodialysis who was receiving what appeared to be an appropriately adjusted dose of acyclovir.