To quantify the risk of prostate cancer after colorectal cancer and the risk of colorectal cancer after prostate cancer and to examine the impact of radiation therapy on subsequent cancer risk, we conducted retrospective cohort studies using data from the Surveillance, Epidemiology and End Results program from 1973 to 2005. Standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) were calculated, adjusting for age, ethnicity, and calendar year. The subsequent risk of developing a prostate cancer was significantly elevated in patients diagnosed with colon cancer before age 50 years (SIR, 1.38; 95% CI, 1.18-1.60). The risk of subsequent prostate cancer was decreased for men with rectal cancer who received radiation therapy (SIR, 0.57; 95% CI, 0.52-0.63). Interestingly, this beneficial effect of radiation therapy was only observed in the prostate-specific antigen (PSA) era (1988+). In addition, the prostate cancer cases developed in the radiation therapy group tended to have higher-grade, later-stage tumors, higher PSA levels, and worse survival than those developed in the nonradiation therapy group. In the cohort of prostate cancer patients, the risk of colon cancer was elevated in patients diagnosed with prostate cancer before age 50 years (SIR, 1.51; 95% CI, 1.03-2.20). In conclusion, a diagnosis of colon or prostate cancer in men of younger ages may be an indication for screening of prostate or colon cancer, respectively. The decreased prostate cancer risk in men who received radiation therapy for rectal cancer may be related to the use of PSA for prostate cancer screening or the cure of occult prostate cancer.