The high microsatellite instability (MSI-H) is frequently observed in localized colorectal adenocarcinoma. MSI-H is a good prognostic factor in nonmetastatic colon adenocarcinoma. However, MSI-H is not a predictive factor because it is not related with better survival in patients with colon cancer with adjuvant chemotherapy. MSI-H should be a predictive factor because it is associated with a higher expression of enzymes, which are inhibited by cytotoxic agents. Here, we analyze this controversy. We conclude MSI-H is not a predictive factor because the adjuvant therapy based on traditional cytotoxic agents does not act on either immune signaling pathways or BRAF mutation.