Squamous cell carcinoma (SCC) of the neovagina after genital reconstruction surgery is a rare occurrence with only very few cases published up to the present. We report a case of a 43-year-old transgender woman who developed neovaginal SCC 23 years after vaginoplasty. The patient tested positive for high-risk human papillomavirus (HPV). At the time of diagnosis, radiological investigations revealed already existing lymph node and osseous metastases. The treatment consisted of various cycles of chemotherapy and radiation therapy. Unfortunately, the formation of additional metastases, including cerebral, pulmonary, and hepatic metastases, could not be prevented. After comparing the literature on the topic, we conclude that neovaginal carcinoma often appears years and decades after genital reconstruction surgery. We therefore recommend the continuation of regular clinical follow-up for transgender women after postoperative follow-up is completed. With this approach, potential lesions may be detected at an earlier stage and a better outcome may be achieved. Follow-up should include neovaginal examination and cytological smear testing. At a later age, we recommend additional regular prostate-specific antigen (PSA) testing and digital rectal examination (DRE). Moreover, transgender women are advised to take part in mammography screening starting at the age of 50, especially when additional risk factors are present.