Background: Viral reactivation in patients undergoing immunosuppressive therapy after hematopoietic stem cell transplantation (HSCT) is a serious complication associated with significant morbidity and mortality. Infections caused by human herpes viruses such as herpes simplex virus (HSV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) can result in oral lesions. Case Presentation: A 40-year-old male patient who had undergone HSCT presented with ulcerated lesions in different areas of the mouth, for 7 months. The lesions had evolved to painful exophytic nodules with an erythematous, ulcerated surface. They were present on the tongue margins and soft and hard palate.Histological, immunohistochemical (IHC), and polymerase chain reaction analyses were performed, and the results were compatible with HSV-1 and -2 and CMV infections. Treatment comprised five sessions of antimicrobial photodynamic therapy (aPDT) and oral valganciclovir. Thirty days after combined antiviral therapy and aPDT, the lesions were completely resolved. Patient was followed up for 12 months without recurrence. Conclusion:Diagnosis and treatment of atypical oral infections in immunosuppressed patients is challenging. Assessment of both clinical and laboratory findings is mandatory for a conclusive diagnosis. The use of local antimicrobial and systemic therapies contributes to positive clinical response in such cases.

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