Background: TIL density reflects the anti-tumor immune response; tumor budding indicates an epithelial to mesenchymal transition (EMT). We determined if these features are prognostic in a single colon cancer (CC) stage with known DNA mismatch repair (MMR) status. Methods: TIL densities (per HPF) and tumor buds (per .785 mm² field) were quantified at light microscopy in 1,532 CC. Tumor budding at invasive margin was defined as single or cluster of ≤ 4 tumor cells. We divided the cohort into training and validation sets. Optimal cutpoints were identified; associations with 3-year disease-free survival (DFS) were evaluated by multivariable Cox regression. Results: TIL and tumor budding cutpoints identified in training set were confirmed in validation set for prognosis. Patients whose tumors had low (≤ 3) vs high TILs were significantly more likely to have higher T, N stage, low histologic grade, left sidedness, worse performance status, non mutated BRAF, and proficient (p) MMR. Tumors with high budding ( > 3) had higher T, N stage; most had pMMR. Overall, significantly shorter DFS was found for tumors with low TILs [HR_adj= 1.74 (95% CI 1.35, 2.24), p < .0001], or with high budding [HR_adj= 1.37 (1.13, 1.67), p = .0011]. When combined, low TILs plus high budding showed poor DFS [HR_adj= 2.07 (1.50, 2.88), p < .0001]. Similar results were found for pMMR tumors (Table). Within dMMR, patients whose tumors had low (≤ 3) vs high TILs had significantly shorter DFS (HR_adj= 2.14; p = .0173); budding was not prognostic (Table). Conclusions: Low TILs and high budding were each validated as markers of poor prognosis in FOLFOX-treated stage III CC, indicating that reduced anti-tumor immunity and an EMT phenotype increase tumor aggressiveness. Whereas TILs and budding each stratified pMMR tumors by DFS, only TILs were prognostic in dMMR tumors and identified the subset with poorest survival.