The purpose of the study was to evaluate the safety and efficacy of percutaneous ultrasound (US) guided radiofrequency ablation combined with percutaneous ethanol injection to treat hepatocellular carcinoma in presumably high-risk locations.Methods: Between September 2013 to December 2016, A total of 69 hepatocellular carcinoma patients with 76 nodules in high-risk locations, defined as less than 0.5cm from a large vessel or an extrahepatic organ, who underwent US-guided percutaneous radiofrequency ablation, combined with percutaneous ethanol injection, were retrospectively assessed. One or two radiofrequency electrodes were inserted and placed at designated places in the tumor. One ethanol needle was placed at the tumor periphery near the high-risk location. Absolute ethanol was injected into the tumor before radiofrequency ablation.. The safety and efficacy of the therapy were assessed by clinical data and imaging in follow-up examinations.Results: All tumors were completely treated with one or two sessions; 61 tumors underwent one session; 15 tumors underwent two sessions. The primary technique was effective in 73 (96.1%) tumors, according to computed tomography (CT) or magnetic resonance imaging (MRI) follow up. No patients had major complications. Two (2.9%) patients died of primary disease progression that was not directly attributable to radiofrequency ablation. Local tumor progression was noted in 3 (3.9%) tumors in the follow-up period. The locally progressing tumors underwent additional therapy (one patient underwent radiofrequency ablation and transcatheter arterial chemoembolization, another patient with 2 nodules underwent transcatheter arterial chemoembolization).Conclusions: US-guided percutaneous radiofrequency ablation, in combination with percutaneous ethanol injection, is a safe and effective treatment for hepatocellular carcinoma in high-risk locations.