The aim of this study was to investigate the influence of combining thymidylate synthase (TS), X-ray cross complementing factor 1 (XRCC1) and uridine diphosphate glucoronosyltransferase (UGT1A1 *28) polymorphism genotypes in response rate and time to progression (TTP) in metastatic colorectal cancer patients treated with 5-fluorouracil (5-FU) plus irinotecan or oxaliplatin (OXA). PCR, RFLP, allelic discrimination and direct sequencing were performed to elucidate TS, XRCC1 and UGT1A1 *28 genotypes in blood from 71 patients. Patients with a number of favourable genotypes (NFG) > or =1 had a lower progression rate and a better TTP than patients with NFG=0 (log-rank p<0.03). In the OXA + 5-FU group, patients with the TS 5' single nucleotide polymorphism and/or XRCC1 genotypes favourable to treatment had a better TTP (log-rank p=0.02). The TS 5' tandem repeat polymorphism and the NFG were independent prognostic factors in the Cox-based multivariate analysis (p<0.03). These results confirm the influence on patient out-come of these genetic polymorphisms and the possibility of studying them together to predict the outcome in first-line treated colorectal cancer patients.