Background: Neoadjuvant multimodality treatment is frequently applied to improve the poor prognosis associated with locally advanced esophageal cancer. However, only patients with a major histopathologic response benefit from this therapy. Predictive markers to allow individualization of multimodality treatment could be very helpful. No non-invasive molecular marker exists that can reliably predict response to neoadjuvant therapy in esophageal cancer. The goal of this study was to determine the value of TS and DPD RNA expression in peripheral blood of patients with locally advanced cancer of the esophagus as a non-invasive molecular predictor of response to neoadjuvant radiochemotherapy. Material and methods: A total of 29 patients with locally advanced cancer of the esophagus were included in this study. Blood samples from each patient were drawn prior to neoadjuvant radiochemotherapy. After extraction of cellular tumor-RNA from blood samples, quantitative expression analysis of TS and DPD and the internal reference gene β-actin was done by real-time RT-PCR (Taqman©). Histomorphological regression was defined as major response when resected specimen contained <10% of residual vital tumor cells, and minor response with >10% of vital residual tumor cells. Results: Twenty of 29 (68%) of patients showed a minor histopathological response and 9 of 29 (32%) showed a major-response to neadjuvant radiochemotherapy. RNA expression in blood of patients was detectable for TS in 86.2%, for DPD in 96.5%, and in 100% for β-actin. The median TS and DPD expression was not significantly different between minor- and major-responders to therapy. No significant associations were detected between TS and DPD expression levels and patients clinical variables. A high expression level for TS was significantly associated with a minor-response to neoadjuvant treatment (p=0.046), while there was no significant association between DPD and response to therapy. Combined analysis of TS and DPD expression increased the specificity for the prediction of response to 100%. No major responder to therapy had high expression levels for both genes in their peripheral blood.Conclusion: The applied method is technically feasible for the analysis of TS and DPD RNA expression in peripheral blood of patients with locally advanced cancer of the esophagus. Quantitation of TS and DPD in peripheral blood appears to be highly specific to identify a subset of patients non-responding to neoadjuvant radiochemotherapy, and could be applied to prevent expensive, noneffective, and potentially harmful therapies in a substantial number of patients with esophageal cancer.