Evidence is accumulating that herpes simplex virus (HSV) infection is implicated in oncogenesis. HSV antigens have been observed in some oral cancers. We present the case of a 62-year-old man who presented with dysphagia, odynophagia, and dysphonia and who was found on computed tomography (CT) to have a mass in his piriform sinus. We suspected a malignancy, but histopathology of biopsy specimens revealed that the mass exhibited the classic signs of the HSV cytopathic effect, including the presence of intranuclear inclusion bodies, ballooning degeneration of epithelial cells, and a ground-glass appearance of some nuclei. The patient responded well to antiviral therapy, and posttherapy CT revealed that the mass had resolved completely. To the best of our knowledge, this is the first report in the literature of a case of HSV infection presenting as a piriform sinus mass.