Background: Doxorubicin-loaded drug-eluting beads TACE (DEB-TACE) has been developed to maximize the therapeutic efficacy of conventional trans-catheter arterial chemo-embolization (cTACE) in patients with hepatocellular carcinoma (HCC); however, its cost-effectiveness (CE) still needs to be assessed. Aims: To investigate the CE of DEB-TACE versus cTACE. Methods: Results from a meta-analysis of the pertinent literature were used to construct a CE Markov simulation model which followed a hypothetical cohort of HCC patients who underwent DEB-TACE or cTACE, covering the entire post-TACE lifespan until death. Costs were assessed from the health-care provider perspective. Results: Five randomized controlled trials (RCTs) and 11 observational studies, including 1860 patients (883 DEB-TACE and 977 cTACE), were used for the construction of the model. Considering only survival rates from RCTs (heterogeneity: 0%), DEB-TACE returned 4.0 quality-adjusted life-years (QALYs) and TACE returned 3.3 QALYs (effect size = 1.288). Total costs of cTACE were €10,389 and those of DEB-TACE were €11,418 (effect size = 0.791). DEB-TACE was found more cost-effective than cTACE when a minimum willingness-to-pay of about €2000-3500/QALY was accepted, mainly depending on shorter in-hospital stay and better quality of life. Conclusions: Direct incremental costs of DEB-TACE can be acceptable in respect to cTACE, relying on financial resources available from the payer perspective.