Circulating tumor DNA (ctDNA) represents a powerful measure of minimal residual disease (MRD) in colorectal cancer (CRC). Although immunotherapy has been widely established in metastatic CRC that is mismatch repair deficient or microsatellite instability-high (dMMR/MSI-H), its role in non-metastatic CRC is rapidly evolving. In resected, dMMR/MSI-H stage II CRC, adjuvant fluoropyrimidine has no benefit and is not recommended. There is growing evidence to suggest diminished benefit from neoadjuvant chemotherapy and chemoradiation in localized CRC that is dMMR/MSI-H. We present two cases of dMMR/MSI-H stage III CRC treated with definitive surgery wherein adjuvant oxaliplatin-based chemotherapy led to a failure to clear postoperative plasma ctDNA levels, prompting a change to immune checkpoint blockade with pembrolizumab and resultant ctDNA clearance. We illustrate that chemotherapy may achieve suboptimal disease control in localized colon cancer that is dMMR/MSI-H, while plasma ctDNA offers a window of opportunity to gauge the efficacy of oxaliplatin-based adjuvant chemotherapy to clear microscopic disease in resected, dMMR/MSI-H stage III colon cancer. These findings are important to contextualize given that relapse is inevitable with failure to clear MRD in the postoperative stage I-III CRC setting whereby chemotherapy remains the standard adjuvant therapy in resected, dMMR/MSI-H stage III colon cancer.