A 56-year-old woman presented with a painless lesion on the inner aspect of her upper lip. The clinical differential diagnoses were oral syphilitic chancre, tuberculosis, histoplamosis, and neoplasia. A biopsy was performed, and the histopathologic diagnosis revealed an eosinophilic ulcer of the oral mucosa. Based on this case, we discuss the history, mechanisms of pathogenesis, clinical manifestations, histopathology, differential diagnosis, and therapy of eosinophilic ulcer of the oral mucosa.