The purpose of this study was to ascertain the possible protective effect of thymostimulin (TS) on chemotherapy-induced leukopenia and related febrile episodes, beside the potential of improving therapeutic efficacy and tolerability of high-dose folinic acid (FA) plus fluorouracil (FU) in metastatic colorectal cancer. In 211 evaluable patients the objective responses were 19/105 (18%) in the FA-FU arm versus 32/106 (30%) obtained with the same regimen plus TS. The difference was statistically significant (p = 0.02). No difference was observed in terms of hematological toxicity, while the TS treated patients experienced a significantly lower incidence of mucositis and diarrhoea (p = 0.03). No significant differences were recorded in the incidence of febrile episodes and other treatment-related toxicities. The possibility of improving response to chemotherapy in advanced colorectal cancer without increasing systemic toxicity is particularly interesting and deserves further attention.