PIP: It is estimated that 2 million US women used diethylstilbestrol (DES), a nonsteroidal estrogen, to reduce the risk of fetal loss from the late 1940s through the early 1960s. The results of clinical trials of the effectiveness of DES in the early 1950s precipitated the eventual decline of DES prescription by the 1960s. Concern about the breast cancer risk associated with the high dose of stilbestrol used led to 2 follow-up studies of these clinical trial participants, as well as 2 other retrospective cohort studies to examine the subsequent risk of breast cancer in DES-exposed women. 3 of the 4 studies reported positive results, with an overall 50% increase in risk for ever using DES during pregnancy and an apparent latency period of more than 20 years. These studies have or more limitations, including the absence of information on dosage taken and duration of use, confusion about the identify of the exposed group and the inability to distinguish between the effect of DES and the effect of indications for using DES. Nevertheless, the findings supported a possible association between DES and breast cancer risk. The 4 studies were published between 1980 and 1984 and included many women who had only recently entered the age period when breast cancer incidence is high. It is possible that the incidence of breast cancer associated with DES may increase with additional follow-up time. Prenatal influences on carcinogenesis have recently become of interest in the etiology of adult cancer, and, in particular, it has been proposed that increased estrogen levels during pregnancy might increase the probability of breast cancer in daughters. It has been demonstrated that DES use during pregnancy can influence the subsequent risk of clear cell adenocarcinoma in offspring, although the issue of whether DES might also influence the subsequent risk of breast cancer in daughters remains to be investigated.