The benefits from medical treatment in colorectal cancer are limited. Fluorouracil remains the only recognized drug, and how to treat unresponsive patients is still debated. To evaluate the role of folinic acid (FA) in circumvence resistance in colorectal cancer, 28 patients pretreated with fluoropyrimidine were candidated to receive one of the following schedules: fluorouracil (600 mg/m2) associated with FA (500 mg/m2) weekly for 6 weeks (Regimen A: 21 cases), or fluorouracil (370 mg/m2) plus FA (200 mg/m2) daily for 5 days every 4 weeks (Regimen B: 7 cases). Fourteen patients were pretreated with doxifluridine, a new fluoropyrimidine derivative with a peculiar mechanism of action, and the remaining 14 patients with fluorouracil. All but 2 patients were unresponsive to first-line treatments. When the treatment began, the median age of the patients was 60 years (range, 30-68). The performance status (ECOG) was 0/1 in 25 of them, and the primary tumor was in the colon and rectum in 19 and 9 patients, respectively. Sites of disease were liver (64%), lung (35%), local recurrence (10%) and peritoneum (10%). A median of 3 cycles (range, 1-7) was delivered, and no objective response was observed in the group of patients pretreated with doxifluridine or in the group pretreated with fluorouracil. In 5 cases a significant decrease in baseline CEA values was observed. Therapy was well tolerated, and no grade 4 toxicity was encountered. Severe toxicity was limited and included diarrhea (7 patients), stomatitis (1 patient) and nausea/vomiting (1 patient). High-dose FA has no role in reversing resistance to fluoropyrimidine, and other mechanisms of refractoriness are surely involved. FA should be associated with fluoropyrimidine as first-line therapy together with other biochemical modulators. Further rescue therapies need to be developed.