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Importance: At present, patients with colorectal cancer (CRC) are risk stratified using TNM histologic features. More recently, an association between a mesenchymal phenotype and a high risk of disease recurrence and micrometastases has been recognized.Objective: To investigate the association of the epithelial to mesenchymal transition (EMT)-inducing transcription factor ZEB2 (zinc finger E box-binding homeobox 2), survival outcomes, and the efficacy of ZEB2 as a biomarker when added as refinement to TNM staging after curative intent surgery for CRC.Design, Setting, and Participants: ZEB2 expression was assessed using a previously validated scoring system as part of a prospective, observational, masked diagnostic study from January 1, 2008, to December 31, 2013. Data were prospectively collected and analyzed for association with oncologic outcomes from January 1, 2017, to December 31, 2018. An initial test cohort from an academic university medical center of 126 consecutive patients with CRC and, subsequently, an independent validation cohort of 210 patients were examined. ZEB2 positivity was scored by 2 independent, masked pathologists. External validity was tested using an open access gene expression portal. Nomograms were developed with or without ZEB2.Main Outcomes and Measures: Systemic and local recurrence of CRC.Results: The test cohort consisted of 126 consecutive patients (mean [SD] age, 72.7 [11.7] years; 61 [48.4%] male) and the validation cohort of 210 patients (mean [SD] age, 72.0 [10.6] years; 111 [52.9%] male). A total of 52 tumors (41.3%) in the test cohort and 104 (49.5%) in the validation cohort were scored nuclear ZEB2 positive. Survival analysis by the log-rank test found that ZEB2 expression was associated with a significant reduction in overall survival and disease-free survival in both cohorts. Cox proportional hazards regression analysis highlighted ZEB2 as an independent biomarker of shorter overall survival and disease-free survival. Analysis of node-negative disease (n = 222) identified ZEB2 as an independent biomarker of early recurrence and reduced survival. External validation confirmed these findings. Addition of ZEB2 expression to nomograms composed of conventional TNM risk factors improved the ability to identify patients at high risk of recurrence demonstrated by the improvement in concordance index in both test (0.73 to 0.77) and validation (0.82 to 0.87) cohorts.Conclusions and Relevance: The findings suggest that expression of ZEB2 is associated with poor oncologic outcome and distant recurrence. The study also found that the addition of ZEB2 to existing TNM classification improved the ability to stratify patients for risk of recurrence. The results of this study suggest that addition of ZEB2 expression status to the TNM staging system improves the ability to stratify patients at high risk of recurrence.