Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, also known as Mullerian agenesis, is a largely sporadic disorder resulting in absence or hypoplasia of the vagina, uterus, and fallopian tubes. In order to foster adequate psychosocial development and sexual intercourse, a number of surgical procedures are available, one of which is the creation of a neovagina from a segment of sigmoid colon. In this report, we describe a patient who presented at age 17 amenorrhea and was found to have MRKH. She underwent vaginal reconstruction with a neovagina from a segment of her sigmoid colon at age 19. Subsequent to this procedure, the patient developed carcinoma of the breast and renal cell carcinoma, and in addition developed an invasive mucinous adenocarcinoma of her neovagina. This is only the third case of an adenocarcinoma arising in a neovagina in the setting of MRKH, and the first case described with an accompanying adenomatous component. All three cases to date demonstrated a mucinous phenotype. Overall, this case emphasizes that neovaginal mucosa may undergo neoplastic transformation, and that recognition of this possibility is important in long-term follow up care for patients affected MRKH treated by surgical reconstruction.