Several reports on fluorouracil (5-FU) and alfa interferon (IFN-alpha) combination therapy in patients with advanced colorectal cancer have been published. In our study high-dose continuous infusion 5-FU (60 mg/kg per 48 hours), oral folinic acid (FA) (8 x 90 mg during 5-FU), and IFN-alpha three times weekly were combined. Because the addition of IFN-alpha has not been tested before, and serious toxicity of 5-FU plus IFN-alpha therapy has been reported, the IFN-alpha dose was escalated from 3 to 10 million units (MU)/dose in the first 11 patients. Grade 3 toxicity was noted in four patients, and consisted mainly of oral mucositis. No grade 4 toxicity occurred. Three partial responses were noted. Preliminary results of a phase II study, in which all patients received IFN-alpha at 10 MU/dose, show grade 3 and 4 toxicities in 24% and 4% of patients, respectively. This compares favorably with other trials in which 5-FU and IFN-alpha was used without FA.