Unresectable biliary tract cancers have a very poor prognosis. No good systemic chemotherapeutic regimen is available. This study aimed to evaluated the activity and toxicity of a novel approach of combined loco-regional and systemic chemotherapy. Twenty four patients with advanced or metastatic biliary tumors were treated with epiadriamycin 50 mg/m2 and cisplatin 60 mg/m2 administered bolus in proper hepatic artery on day 1, combined with systemic continuous infusion of 5-fluorouracil 200 mg/m2/day, from day 1 to day 14, every 3 weeks. The overall response rate was 8/24 (33%), including one complete response and 7 partial responses (stable disease 46%, progression 21%). The treatment was well tolerated with a minimal hematological toxicity; the major clinical problem was the deep venous thrombosis related to central venous catheter, that occurred in 5 patients (21%). Median overall survival was 14,6 months and 1-year and 2-year survival were 54% and 38% respectively. Performance status improved in 33% of patients and weight gain more than 7% was observed in 17%. This novel combined loco-regional and systemic chemotherapeutic regimen is active and safe for advanced biliary tract cancer patients.