OBJECTIVES: To estimate in a pilot study the risk of being diagnosed with prostate cancer after exposure to Agent Orange in a clinical population of military veterans. Prostate cancer is the most common cancer diagnosed in American men and the second leading cause of cancer deaths. An association between Agent Orange and prostate cancer has been suggested by epidemiologic studies. METHODS: A case-control study was conducted at the Department of Veterans Affairs Medical Center in Ann Arbor, Michigan. Cases of pathologically diagnosed prostate cancer were identified and age matched in a 1:3 ratio with controls. Exposure to Agent Orange was assessed by reviewing the administrative portion of the computerized medical records. A subanalysis of the cases was conducted to examine the clinical features of prostate cancer in men reporting exposure to Agent Orange versus those who did not report exposure. RESULTS: A total of 47 military veterans with prostate cancer and 142 control men without prostate cancer were selected. After adjusting for age and race, men with prostate cancer were approximately two times more likely to report previous exposure to Agent Orange (odds ratio 2.06; 95% confidence interval 0.81 to 5.23). CONCLUSIONS: The results from this pilot study suggest exposure to Agent Orange is associated with an increased risk of prostate cancer. Additional study in larger populations is necessary to confirm and to quantify this association more accurately.