The effect of estrogen treatment on risk for cholecystectomy, cholelithiasis, peptic ulcer, and other disorders was investigated using autopsy data from a study of patients randomized to hormonal therapy for prostatic cancer. Treatment with diethylstilbestrol, a nonsteroidal estrogen, was associated with an increased number of cholecystectomies but was unrelated to the presence of cholelithiasis at autopsy. These findings support previous reports of an association between steroidal estrogen use and cholecystectomy, but the risk estimate was more than three times that previously reported. Despite this risk and ample experimental evidence demonstrating that estrogen increases bile lithogenicity, no relationship between estrogen use and cholelithiasis was observed. The absence of such a relationship could not be readily explained by the study size, dose, or duration of estrogen treatment, treatment after leaving the study, or the frequency of preexisting stones. Given these findings the increases cholecystectomy risk may have resulted from estrogen related symptomatology mimicking gallbladder disease or an actual pathophysiologic effect of estrogen on the gallbladder, perhaps involving impaired emptying. In addition, estrogens, orchiectomy, or both were associated with a decreased frequency of peptic ulcer, supporting reports of the efficacy of estrogen in the treatment of peptic ulcer.