Oxaliplatin showsin vitroandin vivosynergism with 5-fluorouracil (5-FU). In this study we evaluate the clinical efficacy of oxaliplatin and 5-FU in heavily pretreated metastatic breast cancer. Eligible patients had to be pretreated with both anthracyclines and taxanes. Pretreatment with capecitabine was recommended but not mandatory. Chemotherapy: oxaliplatin 85 mg/m2/2 h day 1, folinic acid 400 mg/m2/2 h day 1, 5-FU 400 mg/m2i.v. push day 1, 5-FU 2400 mg/m2continuous infusion/48 h day 1, q2w. Fourteen patients were included: one male and 13 females; age: median 53 years (38–62); ECOG 0: three patients, 1: nine patients, 2: two patients; all patients were pretreated with anthracyclines and taxanes, capecitabine: nine patients, vinorelbine: six patients, trastuzumab: four patients, hormonal therapy: 12 patients; lines of prior palliative chemotherapy: 0: one patient, 1: three patients, 2: one patient, 3: three patients, 4: four patients, 5: two patients. Results: median number of cycles: 8 (range 1–17). Toxicity (14 patients evaluable; no. of patients with Common Toxicity Criteria grade 3/4): asthenia: 2/–, paraesthesia 3/–, leuko/neutropenia: 1/2, no neutropenic fever, other (alopecia, skin): 2/–. Response (12 patients evaluable, all with bidimensionally measurable disease): complete remission: no patients, partial remission: four patients (33%, all confirmed), stable disease: five patients, progressive disease: three patients. We conclude that despite the small number of patients, the combination of 5-FU and oxaliplatin shows promising efficacy in this heavily pretreated population.