Background: Randomized phase III trials have shown that patients with dMMR/ MSI-H stage II colon cancer (CC) do not benefit from adjuvant chemotherapy. However, a subgroup of stage II patients have a higher risk for recurrence but it is unclear whether those patients who also have dMMR/MSI-high tumors will in fact benefit from adjuvant chemotherapy. Methods: In this retrospective analysis of National Cancer Database (NCDB) we studied the impact of adjuvant chemotherapy in high risk stage II with dMMR/MSI-high CC. Higher risk was defined by at least one of the following criteria: < 12 lymph nodes examined, lymphovascular invasion (LVI), positive surgical margin, T4 tumor, and poorly differentiated/undifferentiated histology. No data were available for obstruction or perforation at diagnosis. Results: Between 2010 and 2013, 3851 CC patients (56.1% females, median age 69, 49.5% clinico-pathologically high risk) were determined to have dMMR/MSI-high status. 24.6% of dMMR/MSI-high patients received adjuvant chemotherapy, of whom 67.8% received multiagent therapy. On univariate analysis no adjuvant chemotherapy, pT4A/B tumor, pathologic stage IIB/C, < 12 lymph nodes, LVI positive, positive margin, and older age at diagnosis were associated with worse overall survival (OS). On multivariable analysis no adjuvant chemotherapy, male sex, stage IIC, positive surgical margin, older age at diagnosis were associated with worse OS. High risk dMMR/MSI-high patients had better OS when given adjuvant chemotherapy, HR 0.50 (0.34-0.74, p < 001). Single and multiagent adjuvant chemotherapy were associated with better OS, HR 0.38 (0.19-0.76, p = 0.006) and 0.58 (0.37-0.90, p = 0.02), respectively. Conclusions: Adjuvant chemotherapy was associated with better OS in stage II CC patients with high-risk features plus dMMR/MSI-high profile. Benefit was observed with both single and multiagent chemotherapy. In the absence of prospective studies, this study supports the consideration of adjuvant chemotherapy in the subgroup of stage II CC patients with dMMR/MSI-high status if they also have high recurrence clinico-pathological features risk.