Second cancers may occur in patients who have undergone radiation therapy. The risk for these adverse events after therapy is uncertain. In this study, the authors examined the size and significance of the observed association between occurrences of secondary cancers 5 years after radiotherapy in a large population of men with incident prostate cancer. Men with incident prostate cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) registry and were distinguished by the type of treatment received, tumor stage, tumor grade, and age at diagnosis. SEER data also were used to identify occurrences of secondary cancer beginning 5 years after the date patients were diagnosed with prostate cancer. Multivariate logistic regression analysis was used to estimate the adjusted odds of the subsequent occurrence of other cancers associated with types of radiation therapy received and was adjusted for the type of surgery, tumor grade, stage, and patient age. Compared with men who received no prostate cancer-directed radiation, men who received external beam radiation therapy (EBRT) as their only form of radiation therapy had statistically significant increased odds of developing secondary cancers at several sites potentially related to radiation therapy, including the bladder (odds ratio [OR], 1.63; 95% confidence interval [95% CI], 1.44-1.84) and rectum (OR, 1.60; 95% CI, 1.29-1.99). Men who received EBRT also had statistically significant higher odds of developing secondary cancers at sites in the upper body and other areas not potentially related to radiation therapy, including the cecum (OR, 1.63; 95% CI, 1.10-1.70), transverse colon (OR, 1.85; 95% CI, 1.30-2.63), brain (OR, 1.83; 95% CI, 1.22-2.75), stomach (OR, 1.38; 95% CI, 1.09-1.75), melanoma (OR, 1.29; 95% CI, 1.09-1.53), and lung and bronchus (OR, 1.25; 95% CI, 1.13-1.37) compared with the odds among men who received no radiation therapy. Men who received radiation therapy in the form of radioactive implants or isotopes, either in isolation or combined with beam radiation, did not have significantly different odds of secondary cancer occurring at any of the 20 most common sites. Patients who received with EBRT had significantly higher odds of developing second cancers both overall and in the areas that were exposed to radiation. It is noteworthy that, to the authors' knowledge, this report shows for the first time that, despite the higher doses of radiation delivered, patients who received radioactive implants had the lowest odds of developing second cancers.