Background Transcatheter arterial chemoembolization (TACE) and transcatheter arterial infusion chemotherapy (TAI) are increasingly used to treat inoperable liver malignancies. It has not been determined whether standard oral and intravenous administration of antibiotics have different prophylactic effects against post-TACE/TAI infection. We compared the efficacy of oral levofloxacin (LVFX) and intravenous cephazolin (CEZ) in patients receiving TACE/TAI for hepatocellular carcinoma (HCC) using a prospective design. Patients and Methods One hundred twenty-nine eligible subjects with HCC treated by TACE/TAI were analyzed in this study. Patients were randomly assigned by the envelope method to groups who received either intravenous infusion of CEZ at 2 g/day or oral administration of LVFX at 300 mg/day for 5 days. Laboratory data, changes in antibiotic administration from the standard ones, duration of hospital stay, side effects of antibiotics, and infectious complications were assessed. Results There were no significant differences in the WBC counts and serum CRP levels between the groups; there were also no significant inter-group differences in the numbers of infectious and other adverse events. Conclusion Our study findings suggest that the results of peroral administration of LVFX for the prevention of post-procedure infectious complications in patients receiving TACE/TAI for HCC are not inferior to those of intravenous administration of CEZ.