Aim of our work was to assess the role of prognostic and predictive factors in patients to be treated with II and III line chemotherapy in metastatic colorectal cancer.All the patients with metastatic colorectal cancer treated with at least one line of chemotherapy for metastatic disease and progressed after I line chemotherapy were considered eligible and enrolled into the trial.Twenty-six out of 51 consecutive, and potentially eligible patients (51%) were considered eligible and included into the analysis. The median time to progression to I line chemotherapy was 6.7 months with no significant differences between FOLFOX and FOLFIRI (respectively 10 and 6.7 months, p = 0.71). The I line response rate was 57.7% with no significant differences between FOLFOX and FOLFIRI (respectively 46.1% vs 70%, p = 0.4). A significant improve in overall survival was observed for I line responder patients (respectively, 60 and 12 months for responder and non-responder patients, p = 0.0037), with a significant correlation with the time to progression to I line chemotherapy (p = 0.041). No statistical difference was observed for the number of lines of treatment (3 vs 2, p = 0.3), the treatment sequence (FOLFOX--FOLFIRI vs FOLFIRI--FOLFOX, p = 0.94), patient's age (p = 0.105), patient sex (p = 0.055), II line response rate (p = 0.987) and time to progression to II line chemotherapy (p = 0.151) in multivariate analysis.Our data seem to suggest a prognostic significance of I line response rate and time to progression in patients with metastatic colorectal cancer.