Background: The standard adjuvant treatment for patients with stage III colon cancer is 6 months with fluoropyrimidines and oxaliplatin. The Intergroup Trial INT-0035 was the first large-scale study to demonstrate a significant reduction in the risk of death with adjuvant FU plus levamisole in patients with stage III colon cancer. In the MOSAIC study, the addition of oxaliplatin to fluoropyrimidines in patients with resected stage II to III colon cancer showed OS and DFS benefit of oxaliplatin. However, no significant benefit was observed in either DFS or OS in patients with stage II disease, therefore the benefit of adjuvant chemotherapy is still controversial in those patients. Methods: We retrospectively included patients with stages II and III colon cancer that were operated between 2009 and 2014 in the University Ramón y Cajal Hospital from Madrid. We calculate DFS and OS at 48 months and we perform a multivariable Cox model analysis to estimate the benefit of the chemotherapy in each stage. The model was further adjusted by including the following confounders: ECOG-PS, number or removed nodes ( < 12 or ≥ 12), grade and age. A covariate was considered a confounder factor if the difference between the adjusted and unadjusted coefficient of chemotherapy varied > 10%. Stata 13.1 was used to analyze the data. Results: 564 patients were identified (281 stage II and 283 stage III). 259 received chemotherapy and 305 did not. The median follow-up in the entire cohort was 49 months. The median DFS and OS were not reached at the moment of the analysis. DFS and OS at 48 months were both 78.5%. Globally, chemotherapy did not improve DFS (HR 1.05, p: 0.83) but OS was significantly better (HR 0.47, p: 0.001). By stage, chemotherapy did not improve DFS in stage II (HR: 1.6, p: 0.2) nor OS (HR 0.76, p: 0.43). In stage III, chemotherapy showed a trend to improve DSF (HR: 0.61, p: 0.075) and did improve OS (HR: 0.31, p < 0.0001). Conclusions: The multivariable analysis showed a chemotherapy benefit in patients with stage III colon cancer, with a 39% reduction in the risk of recurrence and a 69% in the risk of death; however, in stage II patients these benefits were not found either in DFS or OS.