Abstract Background & Aims Categorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage-independent variability in outcomes. Methods We used a PCR-based assay to detect mutations in BRAF (V600E) and in KRAS in 2720 stage III cancer samples, collected prospectively from patients participating in an adjuvant chemotherapy trial (NCCTG N0147). Tumors deficient or proficient in DNA mismatch repair (MMR) were identified based on detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Findings were validated using tumor samples from a separate set of patients with stage III cancer (n=783). Association with 5-year disease-free survival was evaluated using Cox proportional hazards models. Results Tumors were categorized into 5 subtypes based on MMR status and detection of BRAFV600E or mutations in KRAS, which were mutually exclusive. Three subtypes were MMR proficient: those with BRAFV600E (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAFV600E or mutations in KRAS (49%). Two subtypes were MMR deficient: the sporadic type (6.8%) with BRAFV600E or hypermethylation of MLH1, and the familial type (2.6%), which lacked BRAFV600E or hypermethylation of MLH1. A higher percentage of MMR-proficient tumors with BRAFV600E were proximal (76%), high grade (44%), N2 stage (59%), and detected in women (59%), compared to MMR-proficient tumors without BRAFV600E or mutations in KRAS (33%, 19%, 41%, and 42%, respectively; all P<.0001). A significantly lower proportion of patients with MMR-proficient tumors with BRAFV600E (hazard ratio, 1.43; 95% confidence interval, 1.11–1.85, Padjusted=.0065) or mutant KRAS (hazard ratio, 1.48; 95% confidence interval, 1.27–1.74, Padjusted<.0001) survived disease free for 5 years compared to patients whose MMR-proficient tumors lacked mutations in either gene. Disease-free survival of patients with MMR-deficient sporadic or familial subtypes was similar to that of patients with MMR-proficient tumors without BRAFV600E or mutations in KRAS. The observed differences in survival of patients with different tumor subtypes was validated in an independent cohort. Conclusions We identified subtypes of stage III colon cancer, based on detection of mutations in BRAF (V600E) or KRAS, and MMR status that show differences in clinical and pathologic features and disease-free survival. Patients with MMR-proficient tumors and BRAFV600E or mutations in KRAS had statistically shorter survival times than patients whose tumors lacked these mutations. The tumor subtype found in nearly half of the study cohort (MMR-proficient without BRAFV600E or KRAS mutations) had similar outcomes to those of patients with MMR-deficient cancers.