Case 1 was a 78‒year‒old male with a chief complaint of vertigo. Laboratory data revealed severe renal dysfunction. After admission, he developed incoherent speech and agitation. Case 2 was a 72‒year‒old female who presented with bilateral lower extremity weakness and dysarthria. Her data indicated renal dysfunction, as in Case 1. Neither patient had a history of kidney dysfunction. A few days before hospitalization, they were both prescribed valacyclovir 3,000 mg and non‒steroidal anti‒inflammatory drugs (NSAIDs). Brain CT and MRI revealed no apparent intracranial lesions in either patient. Based on these data, acyclovir‒induced encephalopathy was suspected. Although this drug was discontinued and intravenous fluids were administered, improvements were not seen. In both cases, 2 days after admission, hemodialysis was initiated. The renal function improved, neurological symptoms disappeared, and dialysis was discontinued. Valacyclovir may induce nephropathy or encephalopathy in the elderly with a normal renal function.