Necrotizing ulcerative stomatitis (NUS) is an acute painful ulceronecrotic lesion with red irregular margins, covered with white-greyish smear of the oral mucosa. This lesion is mostly present in immunosuppressed patients such as in leukemia, human immunodeficiency virus (HIV) and malnutrition. This article will discuss the treatment challenges of NUS in patients with HIV and acute myeloid leukemia (AML), and highlight the importance of comprehensive management performed by dental health professionals. A 36-year-old male patient was referred from Hemato-On- cology Clinic to Oral Medicine Clinic Dr. Cipto Mangunkusumo General Hospital with AML and HIV on ART. Intraoral examination revealed multiple ulceronecrotic lesions on some areas of the oral mucosa. Initial laboratory results showed pancytopenia with severe neutropenia and high blast cell percentage, normal CD4+ absolute count and undetected HIV viral load. The oral lesions were diagnosed as NUS based on clinical appearance and the pres- ence of predisposing factors. The treatments were systemic metronidazole 500 mg, oral rinse using 0.2% chlorhex- idine gluconate (CHX) and 3% hydrogen peroxide respectively, and dressing of lip and oral ulceronecrotic lesions using sterile gauze soaked in CHX and 3% hydrogen peroxide respectively, three times a day, and debridement of necrotic tissues on follow up visits. The NUS was frequently relapsed due to uncorrected systemic conditions. The management of NUS can be very challenging in patients with multiple predisposing factors. A comprehensive and in- terdisciplinary approach is necessary in the management of patients with these conditions to prevent complications, progression to Noma and mortality.