Abstract Approximately 20% of individuals diagnosed with colorectal cancer (CRC) in the United States are found to have distant metastases at the time of their diagnosis, indicating an extremely poor prognosis. Although it is well known that primary CRC typically metastasizes to the liver and/or lungs, little is known regarding which factors might explain the anatomic pattern of CRC metastatic spread. Using population-based registry data from the Surveillance, Epidemiology and End Results (SEER) cancer registry of the Seattle-Puget Sound region, we assessed the relationship between primary CRC sub-site and the presence of synchronous metastases in the liver, lungs, and both the liver and lungs. All individuals with stage IV CRC who were diagnosed between 2010-2014 in the 13-county catchment area and who also had complete data on site of metastasis at diagnosis were included in analyses (N = 1287). In total, 703 (55%) patients had distant metastases confined to the liver at the time of diagnosis, 78 (6%) had lung-only metastases, 190 (15%) had metastases in both the liver and lungs but not at other sites, and 316 (25%) exhibited different patterns of metastatic spread, including to the bone, brain, and other anatomic sites. Using multiple logistic regression models, we compared individuals with different patterns of metastatic spread at diagnosis with respect to primary CRC site and with separate models comparing cases with liver-only metastases to all other metastatic cases, comparing cases with lung-only metastases to all other metastatic cases, and comparing cases with metastases to both the liver and lungs to all other metastatic CRC cases. All models were adjusted for age at diagnosis and sex, as well as for depth of primary tumor growth within the colorectum (T-stage) and extent of cancer spread to lymph nodes (N-stage). The odds of having a primary CRC tumor in the rectum, versus proximal colon, were significantly lower among patients with liver-only synchronous metastases relative to those with other patterns of metastatic spread at diagnosis [odds ratio (OR): 0.62, 95% confidence interval (CI): 0.46 - 0.82]. Conversely, the odds of having a primary CRC located in the rectum were significantly higher among those with metastatic disease confined to the lungs (OR: 2.48, 95% CI: 1.38 - 4.47) and those with metastases to the liver and lungs (OR: 1.97, 95% CI: 1.29 - 3.01). Our findings suggest that a patient's site of primary CRC may be informative with respect to possible pattern of metastatic spread. Citation Format: Jamaica R. Robinson, Polly A. Newcomb, Sheetal Hardikar, Stacey A. Cohen, Amanda I. Phipps. Stage IV colorectal cancer sub-site and patterns of distant metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5214.