Purpose <p>We designed this study to evaluate the relationship between radiation proctopathy (RP) and the risk of colon and rectal cancer in prostate cancer patients.</p> Methods <p>This is a retrospective cohort study evaluating patients with prostate cancer who received pelvic radiation therapy between January 2004 and January 2024. The study aims to compare the incidence of post-radiation rectal and colon cancer between patients who developed RP and patients who did not. We excluded patients with a previous history of colon cancer, colectomy, or inflammatory bowel disease.</p> Results <p>In total, 12,629 met the inclusion criteria, 533 patients were diagnosed with RP, and 12,096 were without. We observed a higher incidence of colorectal cancer (3.75% vs. 0.63%), colon cancer (2.06% vs 0.40%), and rectal cancer (1.69% vs 0.23%) in patients with RP compared to those without PR (<i>p</i> &lt; 0.001) during the follow-up period of 81 months for the RP group and 68 months for the non-RP group. PR was associated with colon and rectal cancer with an HR of 4.43 (95% CI, 2.29–8.57; <i>p</i> &lt; 0.0001) and 7.27 (95% CI, 3.43–15.43; <i>p</i> &lt; 0.0001), respectively.</p> Conclusions <p>RP is an independent risk factor for developing rectal and colon cancer after pelvic radiation therapy in patients with prostate cancer.</p>