Background & Aims: Radiation therapy for prostate cancer has been associated with an increased rate of pelvic malignancies, particularly bladder cancer. The association between radiation therapy and colorectal cancer has not been established. Methods: We conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results (SEER) registry data from 1973 through 1994. We focused on men with prostate cancer, but with no previous history of colorectal cancer, treated with either surgery or radiation who survived at least 5 years. We evaluated the effect of radiation on development of cancer for 3 sites: definitely irradiated sites (rectum), potentially irradiated sites (rectosigmoid, sigmoid, and cecum), and nonirradiated sites (the rest of the colon). Using a proportional hazards model, we evaluated the effect of radiation on development of colorectal cancer over time. Results: A total of 30,552 men received radiation, and 55,263 underwent surgery only. Colorectal cancers developed in 1437 patients: 267 in irradiated sites, 686 in potentially irradiated sites, and 484 in nonirradiated sites. Radiation was independently associated with development of cancer over time in irradiated sites but not in the remainder of the colon. The adjusted hazards ratio for development of rectal cancer was 1.7 for the radiation group, compared with the surgery-only group (95% CI: 1.4-2.2). Conclusions: We noted a significant increase in development of rectal cancer after radiation for prostate cancer. Radiation had no effect on development of cancer in the remainder of the colon, indicating that the effect is specific to directly irradiated tissue.