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We evaluated DNA polymorphisms in thethymidylate synthase (TS) and 5,10-methylene-tetrahydrofolate reductase (MTHFR) genes for an association with response and survival in locally advanced gastric cancer treated with 5-FU based preoperative chemotherapy (CTx). DNA of 238 patients (CTx-group: totaln= 135, completely resected (R0)n= 102; without CTx: R0n= 103) was isolated from blood or from nontumorous tissues. In the CTx-group, genotyping of the tandem repeat and the G/C polymorphism in the triple repeat in the promoter region of theTSgene and of the C677T polymorphism of theMTHFRgene was performed. None of the TS or MTHFR genotypes were associated with histopathological response and only the TS tandem repeat polymorphism was significantly related to survival (all patientsn= 135,p= 0.002; R0 resected patientsn= 102,p= 0.007; log-rank test). Multivariate analysis revealed ypN (p< 0.001) and theTStandem repeat polymorphism as independent prognostic factors in the CTx-R0-group (p= 0.003). Analyzing the prognostic significance of theTSpolymorphisms in the R0-group without CTx,TSgenotypes were not significantly associated with survival. Comparing survival between R0 patients with and without CTx in the respectiveTSgenotype groups of the tandem repeat polymorphism, a significant survival benefit for the patients with CTx was found for the 2rpt/2rpt (n= 49;p= 0.002) and 2rpt/3rpt genotypes (n= 99;p= 0.004), but not for the 3rpt/3rpt genotype (n= 57;p= 0.93). Patients' survival after CTx was associated with theTStandem repeat polymorphism. CTx did not improve survival of patients with the 3rpt/3rpt genotype. Thus, a different therapy might be more appropriate for these patients.