Background: Combined use of sorafenib and local therapy for treating unresectable hepatocellular carcinoma (HCC) is not well established. Notably, most common cause of death in HCC is liver failure, therefore we tested the promise of controlling the local tumors even in the setting of advanced/metastatic disease to improve survival. Our study aimed to assess the efficacy and safety of combined use of sorafenib and yttrium-90 resin microspheres (Y90 RMS) in unresectable HCC defined as Barcelona Clinic Liver Cancer class C. Methods: Between October 2013 and August 2016 we enrolled 40 advanced stage HCC patients, 38 patients were treated with sorafenib followed (after 4 weeks) with Y90 RMS at MD Anderson Cancer Center. Survival analysis was done to evaluate median overall survival (OS) and progression-free survival (PFS). We used modified Response Evaluation Criteria in Solid Tumors (RECIST) to assess response to treatment and the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 to evaluate the grading of treatment related toxicity. Results: The majority of our patients were males (74%), white (47%), 66% of patients had underlying liver cirrhosis, 26% had vascular invasion, and 26% had extrahepatic disease. The estimated median OS and 95% confidence interval (CI) in months was 18.46 (12.29 – NA) and the estimated PFS was 12.29 months (5.72 – 18.79). Stable disease (SD) was observed in 44.74% of patients, while 28.95% achieved partial response (PR). Grade III-IV adverse events included fatigue (n = 3), hyperbilirubinemia (n = 2), thrombocytopenia (n = 1), proteinuria (n = 1), hyponatremia (n = 1), elevated liver enzymes (n = 4), hypertension (n = 4), diarrhea (n = 1), nausea (n = 1) and vomiting (n = 2). Conclusions: This is the first prospective study to evaluate sorafenib followed by Y90 in HCC. Our study included patients with metastatic HCC and showed that combined use of sorafenib and Y90 was tolerable and was associated with longer OS and PFS compared to previous studies which evaluated sorafenib alone. However, future randomized phase III studies are warranted to assess sorafenib+/-Y90 in metastatc disease setting. Clinical trial information: NCT01900002