Lonidamine has been demonstrated to potentiate the cytotoxic activity of several antineoplastic drugs, for example anthracyclines. Moreover, epirubicin is considered one of the most active drugs in advanced breast cancer, although optimal dose and schedule remains to be defined. In the present study we have treated 51 patients with advanced breast cancer with a combination of lonidamine (450 mg/day orally from day 1 throughout treatment) and epirubicin (25 mg/m2 i.v.) administered according to a weekly schedule for 24 weeks. Objective responses were observed in 29 out of 51 patients (57%; CR 16%, PR 41%). Liver metastases responded in eight out of 12 evaluable patients (67%). Average response duration was 12.4 months and median overall survival was 23 months (range 1-90+). Toxicity was negligible. The combination of weekly epirubicin and lonidamine is feasible and active in advanced breast cancer patients.