In advanced colorectal cancer the addition of folinic acid (FA) has been shown to lead to increased activity, at least in terms of response rate, in comparison with 5-fluorouracil (5FU) alone. Similarly, interferon-alpha (IFN) is able to potentiate 5FU, although high doses cause heavy toxicity. Given the different mechanisms of action of the two agents, the double modulation of 5FU deserves clinical evaluation. In a multicenter study (involving both primary care and referral institutions) 63 patients with advanced colorectal cancer, previously untreated with chemotherapy, received, in an outpatient setting, FA (200 mg/m2 i.v. bolus) + 5FU (400 mg/m2 i.v. in 15 min) for 5 consecutive days every 4 weeks + IFN 3 x 10(6) U on alternate days, starting 1 week before chemotherapy. During the 5 days of 5FU + FA, IFN was administered daily. The antitumour activity, the impact on response duration and survival and toxicity of the combination were evaluated according to WHO criteria. Of the 63 enrolled patients, 56 were evaluable: there were 2 complete responses (3%) and 13 partial responses (21%), giving an objective response rate of 24% (95% confidence interval 13-35%); no change was observed in 17 cases and progressive disease in 24. Median duration of response was 9 months and median survival (all patients) 13 months. Toxicity was acceptable, even though 4 patients presented reversible grade 4 side-effects (2 mucositis and 2 diarrhoea). With this schedule and these doses, addition of IFN did not lead to any increase in the activity of 5FU + FA. In colorectal cancer, further clinical studies with these drugs should be based on a deeper experimental knowledge of their mechanisms of interaction.