Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil (5-FU)/folinic acid (FA) in intensively pretreated metastatic breast cancer patients prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in a phase I/ II outpatient study. Patients were treated with high-dose 5-FU (by 24-hour infusion) and FA (by 2-hour infusion prior to 5-FU) weekly for 6 weeks (day 1, 8, 15, 22, 29, and 36) repeated every 50 days; in addition, paclitaxel was administered by 3-hour infusion on days 1 and 22. The following dose levels were used in phase 1 of the study. In dose levels 1 through 4, FA was given at a fixed dose of 500 mg/m2, followed by escalating doses of high-dose 5-FU (24-hour infusions of 1.5 [dose level 1], 1.8 [dose level 2], and 2.0 g/m2 [dose levels 3 and 4]). The paclitaxel dose, given over 3 hours on days 1 and 22, was 135 mg/m2 for dose levels 1 through 3 and 175 mg/m2 at dose level 4. Dose level 4 was chosen for further evaluation in the phase II portion of the trial. Among the 46 patients who entered this part of the trial, the median age was 46 years (age range, 26 to 70 years), the World Health Organization performance status was 0 to 1, and the median number of metastatic sites was 2.5 (range, one to four). All patients had bidimensionally measurable disease. Nine patients previously had received adjuvant chemotherapy, 16 had received prior chemotherapy for metastasis, and 21 had been treated with both types of chemotherapy. Of 29 anthracycline-pretreated patients, 25 had anthracycline-resistant disease. Interim results in 35 evaluable patients show complete remission in one patient (3%), partial remissions in 18 (51%), stable disease in 14 (40%), and progressive disease in two (6%). The overall response rate was 54% (95% confidence interval, 36% to 76%). The median number of treatment cycles administered per patient was three (range, one to five), the median time to maximum response was 2 months (range, 1 to 5 months), and the median remission duration was 8+ months (range, 2 to 17 months). Median survival time has not yet been reached. The combination of paclitaxel with weekly high-dose 5-FU/FA was well tolerated in second-line treatment of metastatic breast cancer and results also indicate high efficacy against anthracycline-resistant disease. In an ongoing phase II study we are evaluating the addition of cisplatin to the regimen as first-line treatment of metastatic breast cancer.