Background: Randomized control trials and population-based studies have not demonstrated a definitive benefit for adjuvant chemotherapy in stage II colon cancers. Tumor side and microsatellite instability (MSI) have been proposed as prognostic and predictive factors, but there is little consensus about their utility. Previous studies have been limited by the availability of MSI data. Because microsatellite stability (MSS) is associated with worse prognosis and higher risk of metastases, we hypothesized patients with MSS would have increased benefit from chemotherapy. Methods: Using the National Cancer Database, we preformed a retrospective cohort study of patients with resected stage II colon cancer diagnosed 2006-2013. Patient and disease characteristics were compared with chi-square tests. Survival was evaluated with Cox proportional hazard models. Results: We identified 59,475 patients with stage II colon cancer. 11.4% of patients had known MSI status (n = 6,763) of which 88% had MSS (n = 5,953) and 12% had MSI (n = 810). Patients with MSS were more likely to receive chemotherapy (28.2% vs 19.9%, p < 0.001) and have left-sided tumors (38.8% vs 16.7%, p < 0.001). MSI (adjusted hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.48-0.87; p = 0.003) and receipt of chemotherapy (HR 0.54, 95% CI 0.42-0.69; p < 0.001) were associated with better survival after controlling for multiple characteristics including tumor side. Although left-sided tumors had better survival on univariate analysis (HR 0.91, 95% CI 0.88-0.94; p < 0.001), side was not an independent predictor of survival after controlling for MSI and other characteristics (HR 1.01, 95% CI 0.86-1.20; p = 0.860). Among patients with MSS, chemotherapy remained associated with improved survival (HR 0.54, 95% CI 0.43-0.70; p < 0.001) and this benefit did not vary by tumor side (interaction p = 0.380). There was no interaction between MSI status and chemotherapy (p = 0.139), but we observed less of a survival benefit for chemotherapy in patients with MSI (HR 0.81, 95% CI 0.38-1.75; p = 0.595). Conclusions: Our data suggest a benefit for adjuvant chemotherapy in stage II colon cancer even after adjusting for MSI status. However, tumor side was not prognostic after controlling for MSI status.