Purpose: Colorectal cancer prognosis is currently predicted from pathologic staging, providing limited discrimination for Dukes stage B and C disease. Additional markers for outcome are required to help guide therapy selection for individual patients. Experimental Design: A multisite single-platform microarray study was done on 553 colorectal cancers. Gene expression changes were identified between stage A and D tumors (three training sets) and assessed as a prognosis signature in stage B and C tumors (independent test and external validation sets). For stage C patients, the adjusted hazard ratio was 2.9 (95% confidence interval, 1.1-7.6; P = 0.016). Similar results were obtained for an external set of stage B and C patients. The prognosis signature was enriched for downregulated immune response genes and upregulated cell signaling and extracellular matrix genes. Accordingly, sparse tumor infiltration with mononuclear chronic inflammatory cells was associated with poor outcome in independent patients. Conclusions: Metastasis-associated gene expression changes can be used to refine traditional outcome prediction, providing a rational approach for tailoring treatments to subsets of patients. (Clin Cancer Res 2009;15(24):7642-51) Colorectal cancer is often detected at a stage when complete resection of the primary cancer is possible, yet 40% to 50% of patients who undergo potentially curative surgery alone relapse and die of metastatic disease (1). Patient risk for recurrence is currently largely predicted from the extent of spread of the primary tumor, and this is the major determinant of further clinical management. Although most patients with Dukes stage C (lymph-node positive) cancer receive a combination of 5-fluorouracil and oxaliplatin, adjuvant treatment is offered to only a subset of Dukes stage B (localized disease) patients