To date, conventional treatments for multiple intrahepatic recurrence of hepatocellular carcinoma (HCC) after surgery are unsuccessful. The aim of this retrospective study was to evaluate the prognostic effectiveness of a new infusion chemotherapy of cisplatin (CDDP) and 5-fluorouracil (5-FU) via hepatic artery for HCC with multiple intrahepatic recurrence. Fifty-two patients, who had postoperative multiple recurrence of HCC (more than 3 tumors), were enrolled in this study. Thirty-one patients were treated by hepatic arterial infusion chemotherapy via a subcutaneously implanted injection port. A one-week course of this treatment consisted of daily administration of cisplatin (10 mg for 1 h on days 1-5) and subsequent daily administration of 5-fluorouracil (250 mg for 5 h on days 1-5). Three to six sequential one-week courses were performed (the CDDP,5-FU group). Twenty-one patients underwent conventional interventional therapies including transcatheter arterial chemoembolization, lipiodolization (the conventional group). The complete response rate and the effective response rate in the CDDP,5-FU group were 29.0% and 71.0%, respectively. The 5-year survival rate in this group was 45.7%, which was significantly better than that in the conventional group. Based on multivariate analysis, CDDP,5-FU hepatic arterial infusion chemotherapy was found to be significant in prolonging survival, and this treatment achieved favorable therapeutic results for multiple recurrence of HCC. As part of a multidisciplinary approach this treatment is expected to improve the prognosis of patients with advanced HCC.