Background: We evaluated survival data and local tumor control in 2 groups of patients with hepatocellular carcinoma (HCC) treated with different chemotherapeutic agents for transarterial chemoembolization (TACE). Methods: 28 patients (median age 63 years) with HCC were repeatedly treated with chemoembolization at 4-week intervals. 20 patients had Barcelona Clinic Liver Cancer (BCLC) stage B, while 8 patients obtained chemoembolization for bridging purposes (BCLC stage A). In total, 98 chemoembolizations were performed (median 3.0 treatments/patient). The administered chemotherapeutic agent comprised either mitomycin only (n = 14; 50%) or mitomycin in combination with irinotecan (n = 14; 50%). Lipiodol plus degradable starch microspheres was used for all embolizations. Local tumor response was assessed by magnetic resonance imaging using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Progression-free survival (PFS) was evaluated. Results: In the mitomycin-irinotecan group, complete response (CR) was observed in 21.4%, partial response (PR) in 42.9%, stable disease (SD) in 28.6%, and progressive disease (PD) in 7.1%. In the mitomycin group, PR was observed in 57.2% of patients, SD in 21.4%, and PD in 21.4% (p = 0.043). The PFS of patients after chemoembolization with mitomycin was 4 months compared to the significantly longer PFS of 12 months in the mitomycin-irinotecan group (p = 0.003). Conclusion: Chemoembolization of HCC with mitomycin and irinotecan is the preferred treatment option for achieving local control and better PFS.