BACKGROUND: Electrochemotherapy (ECT) is a local nonsurgical effective tumor treatment in the hand of the clinician for the treatment of patients with liver tumors or metastases. The study aimed to test the technical feasibility and safety of intra-arterial (i.a.) bleomycin administration compared to the established intravenous (i.v.) administration in percutaneous electrochemotherapy (pECT). Furthermore, the equivalence hypothesis was tested between the 2 modalities in terms of local short-term response and progression-free survival. PATIENTS AND METHODS: Forty-four patients have been recruited and treated by pECT for hepatocellular carcinoma, cholangiocarcinoma and liver metastatic lesions from cancers of different origin: 18 were treated with standard i.v., 26 with bleomycin i.a. administration. RESULTS: The 2 groups were similar for anagraphic and anamnestic data, as well as for most relevant disease specific characteristics. Technical success of the treatment was obtained in 95% and 100% of patients in i.v. and i.a. groups respectively. Short-term local response was similar in the 2 groups with a slightly higher complete remission (CR) rate in the i.a. group. There were 61.9% CR, 23.8% partial remission (PR), 4.8% stable disease (SD) in the i.v. group, and 80.6%, CR 12.9% PR, 3.2% PD (p = 0.3454). One-year progression free survival was 60% (C.I. 33%-88%) in the i.v. group and 67% (C.I. 42%-91%) in the i.a. group (p = 0.5849). CONCLUSIONS: The results of this study confirmed the safety and feasibility of super-selective i.a. bleomycin administration. Analysis of local response and progression free survival confirmed the equivalence hypothesis of the new modality compared to standard i.v. administration in the treatment of primary and secondary liver malignancies by pECT.