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Carcinoma of the neovagina is extremely rare, and only one other case has been reported after sex-reassignment surgery. Malignancies seem to be dependent on the original tissue and are thought to be associated with HPV infection or chronic irritation.A 53-year-old male-to-female transsexual presented 21 years after initial surgery with vaginal discharge that was found to be due to a moderately differentiated squamous cell carcinoma. She was treated with chemoradiation with disease remission; however, she had significant stenosis and narrowing of the neovagina.The optimum treatment is unclear, although radiation seems to be the most common technique with surgery an alternative. All patients should have regular clinical follow-up provided by a primary treating unit, which includes pelvic examination and cytologic smears. As a minimum, follow-up should occur as per other vaginal malignancies for at least 10 years.