Background: Activating mutations in the BRAF oncogene (mutBRAF) are associated with deficient MMR (dMMR) in sporadic colon cancers and are mutually exclusive with KRAS mutations (mutKRAS). We evaluated BRAF and KRAS in relation to MMR and disease-free survival (DFS) in stage III pts treated with adjuvant FOLFOX +/-cetuximab; study was amended mid-way to require prospective KRAS testing (Alberts SR, ASCO 2010). Methods: Extracted DNA from archival tumors was analyzed for BRAF exon 15 (V600E) and KRAS exon 2 mutations by allele specific RT-PCR. Tumors with loss of any MMR protein (MLH1, MSH2, MSH6) were categorized as dMMR vs proficient (pMMR). DFS was censored at 4 yrs; median follow-up was 3.1 yrs. Results: Among 2,686 pts, 12% (314/2580) of tumors were dMMR; 28% (716/2579) had mutKRAS, and 14% (346/2515) had mutBRAF of which 43% (150/346) were dMMR. mutBRAF was associated with high grade, proximal site, T_3-4, >4 LNs, and dMMR (all p<0.002); mutKRAS with low grade, proximal, <3 LNs, and pMMR (all p<0.02). Among dMMR tumors, mutKRAS was more frequent in distal vs proximal cancers (28% vs. 8%, p=0.0004). Both mutKRAS (HR=1.42, p=0.0001) and mutBRAF (HR=1.34, p=0.02) were associated with worse DFS and remained significant after adjustment for treatment, MMR, grade, site, T stage and LNs. mutBRAF (p=0.003) and mutKRAS (p=0.003) were each prognostic for DFS in pMMR, but not dMMR tumors (KRAS, p=0.79; BRAF, p=0.60). While MMR was not significant univariately, proximal dMMR tumors had favorable DFS [HR 0.8, 95% CI (0.6-1)] and distal dMMR tumors had poor DFS [HR 2 (1.1-3.4)] after adjusting for KRAS, BRAF, grade, T stage and LNs (p_interaction=0.02). pMMR/mutBRAF (p=0.027) and pMMR/mutKRAS (p<0.001) had worse DFS vs pMMR/bothWT. Conclusions: mutBRAF and mutKRAS were significantly associated with worse DFS independent of treatment, covariates, and each other, with the DFS impact restricted to pMMR tumors. Prognostic impact of MMR was dependent upon tumor site after adjusting for covariates. Support: NIH Grant CA 25224, NCI K05CA 142885, Bristol-Myers Squibb, ImClone, Sanofi-Aventis, and Pfizer.