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Simple Summary: This study addressed the under-investigated issue of second primary cancer occurring in colorectal cancer survivors. Our aim was to explore whether patients recovered from a first colorectal cancer were at higher risk of developing a subsequent primary cancer. The hypothesis was that exposure to cancer treatment, enhanced health surveillance and shared risk factors may lead to an excess risk of second primary cancer in this population. The number of cases of second primary cancer exceeded the expected in this population, mainly driven by female genital cancers, and especially observed in the first years after colorectal cancer diagnosis. Our findings are overall consistent with previous studies, providing valuable information to better characterize and predict mortality from second primary cancer in subjects who suffered from first colorectal cancer. Background: Cancer survivors are at risk of developing second primary cancers (SPC). We investigated the risk of SPC in colorectal cancer (CRC) survivors in Sicily, Southern Italy. Methods: We analyzed data from the Eastern Sicily cancer registry covering 2.5 million people diagnosed and followed up between 2003 and 2017. We calculated the standardized incidence ratio (SIR) and 95% confidence interval (CI) of SPC overall and by cancer type, using the general Sicily population rates as reference. Results: A total of 19,040 cases of CRC and 1453 cases of SPC were included in the analysis. Mean age of occurrence of SPC was 68.1. The SIR for any SPC was 1.11 (95% CI 1.05–1.17); it was higher in women (1.18; 95% CI 1.08–1.29) than in men (1.07; 95% CI 0.97–1.14, p-value of difference 0.07). The SIR was increased for SPC from the ovary (SIR 2.01; 95% CI 1.33–2.95), kidney (SIR 2.00; 95% CI 1.54–2.56), endometrium (SIR 1.94; 95% CI 1.45–2.54), bladder (SIR 1.22, 95% CI 1.04–1.43) and stomach (1.29; 95% CI 0.98–1.66). The SIR for CRC as SPC was 0.84 (95% CI 0.70–1.01). No increased incidence was found for lung, prostate, breast, thyroid and liver cancer. The SIR for SPC overall and several cancers decreased with time of follow-up. Conclusions: In this population, CRC survivors have an 11% higher risk of developing a SPC than the general population, particularly cancers of the ovary, kidney, endometrium, bladder and stomach. Follow-up for SPC is required, especially during the first 5 years from CRC diagnosis. [ABSTRACT FROM AUTHOR]