In this marker evaluation study, we tested whether distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways and DNA repair that predict clinical outcome to 5-fluorouracil (5-FU)/oxaliplatin chemotherapy in patients with advanced colorectal cancer could be identified. Functional polymorphisms in DNA-repair genes XPD, ERCC1, XRCC1, XPA, and metabolising genes glutathione S-transferase GSTP1, GSTT1, GSTM1, and thymidylate synthase (TS) were assessed retrospectively in 106 patients with refractory stage IV disease who received 5-FU/oxaliplatin combination chemotherapy, using a polymerase chain reaction-based RFLP technique. Favourable genotypes from polymorphisms in XPD-751, ERCC1-118, GSTP1-105, and TS-3'-untranslated region (3'UTR) that are associated with overall survival were identified. After adjustment for performance status, the relative risks of dying for patients who possessed the unfavourable genotype were: 3.33 for XPD-751 (P=0.037), 3.25 for GSTP1-105 (P=0.072), 2.05 for ERCC1-118 (P=0.037), and 1.65 for TS-3'UTR (P=0.091) when compared to their respective beneficial genomic variants. Combination analysis with all four polymorphisms revealed that patients possessing > or =2 favourable genotypes survived a median of 17.4 months (95% confidence interval (CI): 9.4, 26.5) compared to 5.4 months (95% CI: 4.3, 6.0) in patients with no favourable genotype. Patients who carried one favourable genotype demonstrated intermediate survival of 10.2 months (95% CI: 6.8, 15.3; P<0.001). Polymorphisms in the TS-3'UTR and GSTP1-105 gene were also associated with time to progression. After adjustment for performance status, patients with an unfavourable TS-3'UTR genotype had a relative risk of disease progression of 1.76 (P=0.020) and those with the unfavourable GSTP1-105 genotype showed a relative risk of progression of 2.00 (P=0.018). The genomic polymorphisms XPD-751, ERCC1-118, GSTP1-105, and TS-3'UTR may be useful in predicting overall survival and time to progression of colorectal cancer in patients who receive 5-FU/oxaliplatin chemotherapy. These findings require independent prospective confirmation.