Introduction: A history of colorectal cancer (CRC) increases the risk of subsequent gastrointestinal (GI) cancer. Cancers of the right colon, left colon, and rectum differ according to molecular profiles, responses to treatment, and outcomes. Objective: The purpose of this study was to determine if CRC location is associated with differential risk for secondary primary GI malignancy. Methods: A retrospective cohort of adults with CRC was compiled using the Surveillance, Epidemiology, and End Results database (1973–2015). Standardized incidence ratios (SIRs) for second primary GI malignancies were compared based on location of the index CRC (right colon, left colon, or rectum). Results: The cohort included 281,413 adults with CRC (30.3% right, 35.3% left, 34.3% rectum). With a median 4.9-year follow-up, 12,064 (4.3%) patients developed a second primary GI malignancy (64% CRC, 36% non-CRC). Those with CRC at any location had higher than expected incidences of small intestine, bile duct, and other CRCs, and lower incidences of liver and gallbladder cancer. The SIR for small intestinal cancer was higher after right colon cancer than after left colon or rectal cancer. The esophageal cancer SIR was higher after left colon cancer. Pancreas cancer was higher than expected for right colon cancer, but lower for left colon and rectal cancer. Conclusion: The location of CRC leads to differences in the incidence and location of second primary GI malignancies and may be related to similarities in the associated carcinogenesis and molecular pathways or response to treatment. CRC location not only impacts treatment response and outcomes, but should also be considered during subsequent surveillance.