Background: XIAP inhibits caspases which are proteases responsible for apoptotic cell death. It is highly expressed in HCC. AEG35156 is a second generation antisense oligonucleotide targeting XIAP mRNA, thus lowers the apoptotic threshold of cancer cells. It also accumulates in the liver. This study is designed to assess the added benefit of combining AEG35156 with sorafenib. Methods: Patients with histologically or clinically diagnosed (AASLD criteria) HCC who had failed or were unsuitable for resection or ablative therapies were randomized (2:1) to receive either weekly injection of AEG35156 300mg in combination with sorefanib 400mg BID or sorefanib alone. The primary end point was progression-free survival (PFS). Other endpoints were overall survival (OS), response rates and safety. Results: 51 patients were recruited. 48 patents were evaluable. There were 31 patients in the combination arm and 17 in the control arm. The median age was 60. 88% of patients were male. 81% of patients were hepatitis B carrier. 90% of patients belong to Child-Pugh class A. The median follow-up was 16.2 months. The PFS for the combination arm was 4.0 months (95% CI: 1.2-4.1) and 2.6 months for control arm. The OS for the combination arm was 6.5 months (95% CI: 3.9-11.5) and 5.4 months for the control arm. There were 3 partial responders (Choi’s criteria) in the combination arm (10%, 95% CI: 3-27%) and none (0%) in the control arm. Patients who had the study treatment interrupted (PFS 4.0, 95% CI: 2.4-5.4) or had dose modification (PFS 4.45, 95% CI: 1.0-6.5) according to protocol did significantly better than those who had no dose reduction (PFS 1.2, 95% CI: 1.2-4.0) and those in the control arm (PFS 2.6, 95% CI: 1.2-5.4). This also applies to OS. Regarding toxicities, there were one AEG35156 related serious adverse event (SAE) of hypersensitivity and two sorafenib related gastrointestinal SAE. Conclusions: AEG35156 in combination with Sorafenib was well tolerated in patients with advanced HCC. Dose reduced AEG35156 in combination with sorafenib have shown more activity than sorafenib alone and warrants further investigation.