OBJECTIVES: Hepatocellular carcinoma (HCC) is a major health problem worldwide. Trans-arterial radioembolization (TARE) is a relatively new option for the management of non-resectable HCC, although not explicitly recommended in clinical guidelines. Other approaches include systemic chemotherapy (i.e. sorafenib) or trans-arterial chemoembolization (TACE). Few studies have shown the favourable cost-effectiveness profile of TARE versus sorafenib, however scant evidence exists about which treatment sequence is best. In this study we evaluated two treatment sequences, TARE followed by TACE and eventually sorafenib (=TTS) and TARE followed by sorafenib alone (=TS) in intermediate stage patients, to identify the most cost-effective pathway from the Italian healthcare system perspective. METHODS: Starting from patient level data collected at three oncology centers in Italy, a Markov model was developed to project costs and health outcomes (life years and QALYs) associated with intermediate stage HCC patients for TTS and TS cohorts over a lifetime horizon (yearly discount rate 3.5%). Healthcare resource utilization was derived from standard management protocols for TARE, TACE and sorafenib. Costs were obtained from DRGs reimbursement rates and official tariffs. RESULTS: Considering 16 patients for TTS (47% with sorafenib administration) and 22 patients for TS treatments, the model estimated an average lifetime cost per patient of 36,509€ and 42,812€, respectively, and 3.494 years (1.385 QALYs) for TTS and 2.361 years (0.937 QALYs) for TS, in terms of health outcomes. TTS sequence resulted as dominant strategy. CONCLUSIONS: The cost-effectiveness of TARE versus sorafenib for the treatment of intermediate-advanced HCC has been previously stated. Our study, performed on a subset of patients with intermediate stage HCC, revealed that TARE followed by TACE plus eventually sorafenib may be a dominant strategy compared to TARE followed by sorafenib alone. Further RCTs and real world data are needed to better characterize the treatment pathways and confirm these conclusions in different settings and jurisdictions.