© 2018 American Association for Cancer Research. Purpose: There are conflicting results concerning the prognostic value of the CpG island methylator phenotype (CIMP) in patients with nonmetastatic colon cancer. We studied this phenotype in stage III colon cancer characterized for mismatch repair (MMR), RAS, and BRAF status, and treated with adjuvant FOLFOX-based regimen. Experimental Design: Tumor samples of 1,907 patients enrolled in the PETACC-8 adjuvant phase III trial were analyzed. The method used was methylation-specific PCR, where CIMPþ status was defined by methylation of at least 3 of 5 following genes: IGF2, CACNA1G, NEUROG1, SOCS1, and RUNX3. Association between CIMP status and overall survival (OS), disease-free survival (DFS), and survival after recurrence (SAR), was assessed by Cox model adjusted for prognostic factors and treatment arm (FOLFOX4 cetuximab). Results: CIMP status was successfully determined in 1,867 patients (97.9%): 275 (14.7%) tumors were CIMPþ. Compared with CIMP patients, CIMPþ patients were more frequently older (P ¼ 0.002), females (P ¼ 0.04), with right-sided (P < 0.0001), grade 3-4 (P < 0.0001), pN2 (P ¼ 0.001), dMMR (P < 0.0001), BRAF mutated (P < 0.0001), and RAS wild-type (P < 0.0001) tumors. In multivariate analysis, CIMPþ status was associated with shorter OS [HR, 1.46; 95% confidence interval (CI), 1.02-1.94; P ¼ 0.04] and SAR [HR, 1.76; 95% CI, 1.20-2.56; P < 0.0004]; but not DFS [HR, 1.15; 95% CI, 0.86-1.54; P ¼ 0.34]. A nonsignificant trend of detrimental effect of cetuximab was observed in patients with CIMPþ tumors for OS, DFS, and SAR. Conclusions: In a large cohort of well-defined patients with stage III colon cancer, CIMPþ phenotype is associated with a shorter OS and SAR but not to DFS.