Multiple ulcers in the oral cavity can be caused by various predisposing factors, including systemic conditions, making it a challenge to diagnose them. The aim of this paper was to discuss the challenges in diagnosing multiple oral ulcers with systemic disease as predisposing factor. A 57-year-old male came to Universitas Indonesia Dental Hospital with the chief complaint of canker sore on the tongue since 3 weeks ago and he had difficulty in speaking. He experience no fever, only sore throat. History of canker sores 2-3 times a year. He smoked 1 pack of cigarettes per day since 35 years ago. Weight loss 3kg in 3 weeks, difficult to swallow. His stomach pain when he eats late. Defe- cate once every 2 days without bleeding. Clinical examination lymph nodes are not palpable and painless. Intraoral there were multiple coalescent ulcers on the buccal and labial mucosa, also minute ulcers on ventral of tongue. The working diagnosis was recurrent aphthous ulcer herpetiformis with differential diagnosis was recurrent intraoral herpes (RIH). The patient was prescribed with mouthwash containing aloe vera and multivitamins plus minerals. To confirm the diagnosis the patient was referred for serological examination of HSV, IgE, complete blood count, liver and kidney function and to the internist for evaluation of systemic conditions The results showed that the patient’s IgG to anti-HSV was increased, the diagnosis was confirmed to be recurrent intraoral herpes. The internist performed an examinations of random blood glucose, HbA1c, albumin, CEA, urinalysis, thorax PA, colonoscopy showed nor- mal results. However, CRP level was high. Gastroscopy and antrum biopsy showed mild active chronic gastritis, non-atrophic, and non-dysplastic. The patient was given gastritis drug therapy, antibiotics and corticosteroids. Oral lesions completely resolved on eight week of follow-up. Early identification of the patient’s systemic condition and appropriate treatment can decreased the severity, increased healing process of RIH, and may improve the quality of life of the patient.