We report an update of our results of a trial of high-dose folinic acid (HDFA) and 5-fluorouracil (5-FU) in advanced breast cancer. Thirty-eight patients with advanced and mainly refractory breast cancer were treated with the following regimen: HDFA (200 mg/m2/day) and 5-FU (340, 370, 400 mg/m2/day) given immediately afterwards, for 5 consecutive days every 4 weeks. Of 36 evaluable patients, 3 achieved complete remission (8%) and 13 partial remission (36%) for an overall response rate of 44%, while 11 patients (30%) had stable disease. Thirteen out of sixteen responders (85%) were pretreated with some 5-FU-containing regimens. The median duration of response was 9.6+ months, the median survival for responders and for patients with stable or progressive disease was 19.9+, 18.8+ and 9 months, respectively. The overall toxicity was acceptable: while hematological toxicity was very mild, oral mucositis, diarrhea and conjunctivitis were major side effects. These results seem very promising and deserve further evaluation.