© 2015 by American Society of Clinical Oncology. Purpose: To report the final efficacy findings and biomarker analysis from the NO16968 trial comparing bolus fluorouracil/folinic acid (FU/FA) with capecitabine plus oxaliplatin (XELOX) in resected stage II colon cancer. Patients and Methods: After curative resection, patients were randomly assigned to receive XELOX, as oxaliplatin 130 mg/m2 on day 1 and capecitabine 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks, or bolus FU/FA, as the Mayo Clinic or Roswell Park regimens, for 6 months. The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS) Results: The intention-to-treat population comprised 1,886 patients (XELOX, n = 944; FU/FA, n = 942) Seven-year DFS rates were 63% and 56% in the XELOX and FU/FA groups, respectively (hazard ratio [HR], 0.80; 95% CI, 0.69 to 0.93; P =.004). Seven-year OS rates were 73% and 67% in the XELOX and FU/FA groups, respectively (HR, 0.83; 95% CI, 0.70 to 0.99; P =.04) A total of 68% and 77% of patients who experienced relapse or a new colorectal cancer in the XELOX and FU/FA groups, respectively, received drug treatment for metastatic disease. Four hundred ninety-eight patients consented to the biomarker analysis: 242 in the XELOX group and 256 in the FU/FA group. Low tumor expression of dihydropyrimidine dehydrogenase may be predictive for XELOX efficacy; in the XELOX group, for high versus low dihydropyrimidine dehydrogenase expression levels, DFS HR was 2.45 (95% CI, 1.55 to 3.86; P <.001), and OS HR was 2.75 (95% CI, 1.65 to 4.59; P >.001). In the FU/FA group, no statistically significant associations were observed between any tumor biomarker and outcomes Conclusion: XELOX improved OS compared with bolus FU/FA in patients with resected stage III colon cancer after a median follow-up of almost 7 years. XELOX should be considered a standard adjuvant treatment option in patients with stage III disease. Tumoral dihydropyrimidine dehydrogenase expression is a promising predictive, and potentially, highly clinically relevant, biomarker for XELOX efficacy requiring further prospective evaluation.