Objective. Our previous studies have documented the feasibility of using the laying hen, Gallus domesticus, as a model of spontaneous ovarian carcinogenesis. This study was performed to determine the ability of medroxyprogesterone acetate (Depo-Provera) to reduce the frequency of spontaneously developing reproductive tract adenocarcinoma in the avian model. Method. Four hundred 3-year-old hens were in a two-arm trial designed to determine the frequency of epithelial reproductive tract adenocarcinomas. Animals were designated to receive three injections of 100 mg Depo-Provera versus no injection over a 16-month period. Both groups were subjected to two induced molts 12 months apart. Egg counts were obtained and decreased egg production was documented in the treated hens due to Depo-Provera. At the end of 16 months surviving animals were sacrificed and the frequency of reproductive tract adenocarcinoma was determined histologicically. Results. Histologic information was obtained from the 293 hens that completed the full prescribed course of study. At the time of necropsy, multiple hens had evidence of carcinomatosis and massive ascites consistent with metastatic reproductive tract adenocarcinomas. Of the tissues examined from the informative cases gathered at the time of sacrifice, there was evidence of a reduction of reproductive tract adenocarcinoma observed in the Depo-Provera group (45/127 - 35%) when compared to the control group (69/166 - 42%). A risk reduction of 15% is observed in the treatment group (risk ratio 0.85: 95% confidence interval 0.63-1.15). Conclusion. The high rate of reproductive tract adenocarcinoma observed in this study supports the avian hen as a valid model of spontaneous ovarian carcinogenesis in which to test chemoprevention strategies and provides a unique opportunity for investigating the pathogenesis of ovarian carcinoma. The current histologic findings are consistent with the theory that a reduction of ovulatory events may prevent the development of ovarian adenocarcinoma. © 2002 Elsevier Science (USA).