Background This study is a multi-centre, open-label, randomised controlled trial that will compare the impact of selective internal radiation therapy (SIRT) using SIR-Spheres® yttrium-90 microspheres versus sorafenib on overall survival in patients with locally advanced hepatocellular carcinoma (HCC). A definitive RCT comparing the 2 most promising therapies in locally-advanced HCC will impact on outcomes in a large number of patients and change clinical practice. This will also pave the way for future trials in combined modality therapies in HCC. Methods The study is structured so that patients with locally advanced HCC, who satisfy the study eligibility criteria, will be randomised to receive either: Treatment Arm A: Oral Sorafenib therapy at a dose of 400 mg b.i.d until disease progression, no further response, complete regression or unacceptable toxicity or Treatment Arm B: A single administration of SIR-Spheres into the liver targeted at HCC in the liver by the trans-arterial route. Results Twenty patients treated with 90Y-RE and nineteen patients received Sorafenib at our institution from 14 March 2011, and 30 June 2016 were included. Data from 39 consecutive patients were analyzed. The majority of patients were Child Pugh class B(90%), Barcelona Clinic liver Cancer(BCLC) stage C(58.5%) and Okuda class I (89.5%). Approximately 71% patients diagnosed in IIIa stage and 70% of patients had HBV infection. In the analysis for best response, three of 20 patients in the SIRT group (15%) achieved a partial response 7 of 19 patients (46%) had stable disease, whereas in Sorafenib group, two of 19 patients in the SIRT group (12%) achieved a partial response 9 of 19 patients (39%) had stable disease. Conclusion This study shows the potential efficacy of SIR-Spheres and sorafenib. In summary, selective internal radiation therapy (SIRT) using SIR-Spheres is a promising treatment for well selected patients with unresectable HCC. Sorafenib is effective for the patients with locally advanced HCC without portal vein thrombosis (PVT).