Objective: Both acyclovir (ACV) and valacyclovir (VACV) can cause drug-induced encephalopathy, which occurs primarily in patients with renal impairment because of delayed drug metabolism. Here, we report a case of ACV-associated encephalopathy precipitated by the addition of nonsteroidal anti-inflammatory drugs (NSAIDs).Patient: A 97-year-old woman with a 1-d history of altered consciousness was admitted to our hospital. After treatment with ACV and VACV for herpes zoster, NSAIDs were introduced for pain 5 d prior to admission. VACV and NSAIDs were subsequently administered by her primary care physician 3 d before admission.Results: The patient presented with altered consciousness and acute kidney injury, leading to a suspicion of ACV-associated encephalopathy. Her consciousness improved rapidly with hemodialysis. We diagnosed ACV-associated encephalopathy based on a significantly elevated ACV blood level of 32.7 µg/dL.Conclusion: The addition of NSAIDs during ACV or VACV administration may precipitate ACV-associated encephalopathy. When combining ACV or VACV with NSAIDs for the treatment of herpes zoster, careful monitoring of consciousness level and renal function is recommended.