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.