Recent studies have shown an association between the GNAS1 T393C polymorphism and clinical outcome for various solid tumors. In this study, we genotyped 51 patients from an observational trial on cisplatin/5-FU-based neoadjuvant radiochemotherapy of locally advanced esophageal cancer (cT2-4, Nx, M0) and genotyping was correlated with histomorphological tumor regression. The C-allele frequency in esophageal cancer patients was 0.49. Pearson's chi(2)-test showed a significant (P<0.05) association between tumor regression grades and T393C genotypes. Overall, 63% of the patients in the T-allele group (TT+CT) were minor responders with more than 10% residual vital tumor cells in resection specimens, whereas T(-) genotypes (CC) showed a major histopathological response with less than 10% residual vital tumor cells in 80%. The results support the role of the T393C polymorphism as a predictive molecular marker for tumor response to cisplatin/5-FU-based radiochemotherapy in esophageal cancer.