To identify a panel of biomarkers that predicts response of esophageal cancers to preoperative chemoradiation, our group profiled the gene expression of pretreatment cancer biopsies from patients with esophageal cancer. Six (32%) of these patients had pathologic complete response. All cancers except one that achieved pathologic complete response (83%) clustered in one molecular type (type I), while cancers that achieved less than pathologic complete response with one exception clustered in another molecular type (type II). Activated NF-κB was significantly associated with aggressive pathology. These data indicate that expression analysis of a limited set of biomarkers selected from the list of genes that were differentially regulated between the two subtypes can increase predictive power, and suggest that esophageal cancer with activated NF-κB may result in poor treatment outcome.