This study aimed to investigate the incidence and the risk factors of incidence for second primary malignancies (SPMs) onset among survivors diagnosed with colorectal cancer (CRC).A large population-based cohort study was performed. Data of patients diagnosed with CRC was identified and extracted from 8 cancer registries of Surveillance, Epidemiology, and End Results database from January 1990 to December 2017. The outcome of interest was percentage and common sites of SPM onset after primary CRC diagnosis. The cumulative incidence and standardize incidence rates (SIRs) were also reported. Afterwards, we estimated sub-distribution hazards ratios (SHRs) and relative risks (RRs) for SPM occurrence using multivariable competing-risk and Poisson regression models, respectively.A total of 152,402 patients with CRC were included to analyze. Overall, 23,816 patients of all CRC survivors (15.6%) were reported SPM occurrence. The highest proportion of SPMs development after primary CRC diagnosis was second CRC, followed by lung and bronchus cancer among all survivors. Also, CRC survivors were more susceptible to develop second gastrointestinal cancers (GICs). Besides, pelvic cancers were analyzed with a relative high proportion among patients who received RT in comparison to those without RT. The cumulative incidence of all SPMs onset was 22.16% (95% CI: 21.82-22.49%) after near 30-year follow-up. Several factors including older age, male, married status, and localized stage of CRC were related to the high risk of SPMs onset. In treatment-specific analyses, RT was related to a higher cumulative incidence of SPMs occurrence (all SPMs: 14.08% vs. 8.72%; GICs: 2.67% vs. 2.04%; CRC: 1.01% vs. 1.57%; all p < 0.01). Furthermore, the increased risk of SPMs onset was found among patients who received RT than patients within the NRT group (SHR: 1.50, 95% CI: 1.32-1.71), p < 0.01; RR: 1.61, 95% CI: 1.45-1.79, p < 0.01).The present study described the incidence pattern of SPM among CRC survivors and identified the risk factors of the SPM onset. RT treatment for patients diagnosed with CRC may increase the risk of SPMs occurrence. The findings suggest the need for long-term follow-up surveillance for these patients.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.