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Reactivation of herpes simplex virus resulting in oral infection is common after cardiac transplantation and usually occurs within the first month posttransplant. The clinical presentation, however, may be atypical. We present a case of a 48-year-old female who presented with a large tongue mass 1 year after cardiac transplantation. Outpatient biopsies and viral stains were nondiagnostic. Because of the high suspicion for malignancy, an excisional biopsy was performed in the operating room. Pathologic analysis was consistent with herpes simplex virus type 1 infection. The patient received antiviral therapy with resolution of infection at follow-up.