We present a patient who underwent male-to-female reassignment, and then developed squamous cell carcinoma during a complicated long-term follow-up. In very rare cases, squamous cell carcinoma may be considered in the differential diagnosis of sustained ulceration in neovaginas constructed by inverting the penile skin in male-to-female reassignments, in particular because clinical examination may be hampered by contractile scar formation of the neovaginal canal. Despite the lack of statistical evidence, it may be assumed that the heterotopic penile skin is at an increased risk of developing HPV-induced squamous cell carcinoma, especially if, over the years, there is a personal history of venereal warts.