PIP: This chapter discusses current knowledge concerning clear cell adenocarcinoma of the vagina and cervix as well as nonmalignant genital alterations in both female and male diethylstilbestrol (DES)-exposed offspring. A special registry on clear cell adenocarcinoma in young women established in 1971 has so far accessioned 400 cases as of December 1979. Analysis of maternal drug histories for 347 cases revealed that 61% had exposure to DES or chemically related dienestrol or hexestrol (nonsteroidal synthetic estrogens), 10% had been treated with unidentified medication for high-risk pregnancy, in slightly more than 25% there was evidence of maternal hormone usage and in about 2.5%, a non-DES type hormone had been used. DES patients ranged in age from 7-29 at time of diagnosis. 95% of the tumors were found in those aged 14 years or older; median age was 18.9 years. It is estimated that the risk of developing clear cell adenocarcinoma of the vagina and cervix in an exposed female up to age 24 is between 0.14 and 1.4 in a thousand. The national cooperative DES adenosis study estimates the risk to be less than 1 in a thousand. These estimates are supported by the observation that the number of DES-associated cancer cases occurring in various birth cohorts in the U.S. (1950 and earlier, 1951-53, 1954-56) closely parallel the sales of 25 mg DES tablets of a major U.S. drug manufacturer. This suggests that occurrence of cancer is related to the frequency of DES use during pregnancy. Overall, the 5-year survival for patients with adenocarcinoma is 78%, which is higher than usually reported for squamous cell carcinoma of the cervix (55%) or of the vagina (35%). Widespread screening evaluation of the DES-exposed female population undoubtedly contributes to the diagnosis of the tumor at an early stage and thus, greater chance for survival. Nonmalignant changes of the DES-exposed female genital tract include vaginal adenosis, cervical ectropion or eversion, squamous metaplasia, metaplastic epithelium, and transverse vaginal and cervical ridges. DES daughters should have a thorough screening examination and close follow-up when they begin to menstruate or by the time they are aged 14 years. The status of DES-exposed mothers and sons is briefly discussed.