Background: Recent studies have reported a survival difference between right colon cancer (RCC) and left colon cancer (LCC) but were limited by lack of data on surgical therapy and underlying tumor biology including microsatellite instability (MSI) status. Our objective was to examine the influence of tumor sidedness on stage-specific survival after adjustment for those factors using a large national database. Methods: Adult patients with primary invasive colon cancer were identified from the National Cancer Data Base (NCDB) between 2009 and 2012. Cecum, ascending colon, hepatic flexure, and transverse colon were classified as “RCC” and sigmoid, descending colon, and splenic flexure were classified as “LCC”. Differences in 3-year overall survival (OS) between RCC versus LCC, stratified by stage, were obtained. Results: Of 24,092 patients, 9,095 (37.75%) presented with a LCC and 14,997 (62.25%) with a RCC. After adjustment for confounding factors, including demographics, MSI, KRAS, nodal retrieval and treatment, patients with RCC stage I, III, or IV had a 31-35% decreased OS compared to those with a LCC. However, in patients with stage II disease, RCC had a 15% improvement in OS compared to LCC (Table 1). MSI positivity was not significantly different in RCC versus LCC stage for stage nor did it contribute to decreased OS for either side. Conclusions: Colon cancer sidedness is an independent risk factor for decreased survival after adjusting for potential confounders including tumor biology and treatment characteristics. For patients with stage I, II, and IV disease, RCC portends a decreased survival compared to LCC, whereas the opposite is true for patients with stage II disease. Further research is needed to elucidate the exact the role of sidedness in risk-profiling and staging for colon cancer patients.