An 81-years-old woman presented multiple mucosa ulcers with a chief complaint of pain during wearing the lower denture. She had been wearing upper and lower complete dentures for five months, and received multiple drugs for the treatment of angina pectoris, constipation, neurosis, hypertension and arthritis (calcium channel blockers, furosemide, captopril, nonsteroidal anti-inflammatory agents and penicillamine, respectively), but no history of immune-diseases and viral infection symptom. The present lesion was primarily diagnosed as traumatic ulcer, candidiasis and lichen planus in the clinical observation, thereby conservatively treated with denture relining, antifungal agent, and steroidal agent. However, the ulcer lesion was not healed for two months and rather increased in size. With the diagnosis of viral infection the immunohistochemical (IHC) staining of IL28 and E6, and polymerase chain reaction (PCR) using herpes simplex virus (HSV)-1 primer sets was done but entirely showed negative reaction. Therefore, with the patient’s medical history and IHC findings exhibiting strong positive reaction of CD3 and CD28, but rare/weak reaction of NFkB, CD20, IgK and p38, the ulcer lesion was finally diagnosed as drug-induced pemphigoid ulceration which was not an inflammatory granulomatous lesion but related to the retrogressive acantholytic degeneration of epithelial cells caused by multiple drug abuse.