This comparative effectiveness review evaluates local hepatic therapies for patients with unresectable primary hepatocellular carcinoma (HCC) who are not candidates for surgical resection or liver transplantation. Here we describe the epidemiology and staging of HCC, as well as currently available treatment strategies. We also discuss the current practice guidelines and the impetus for this review. Hepatocellular carcinoma is the most common primary liver tumor. It is the fifth most common cancer and the third leading cause of cancer death worldwide. Overall 5-year survival rates for HCC are less than 10 percent in Europe and the United States. The main etiology of HCC is chronic infection with the hepatitis B and hepatitis C viruses. Approximately 4 million individuals in the United States are chronically infected with hepatitis C virus, and the annual incidence rate of HCC among patients with hepatitis C-related cirrhosis is estimated to be between 2 and 8 percent. Unlike the case with most solid tumors, the incidence of and mortality rate due to HCC are projected to increase worldwide in the next 20 years, primarily due to the dissemination of hepatitis C virus infection.Other causes include cirrhosis due to any cause (e.g., alcohol), hereditary hemochromatosis and iron overload syndromes, nonalcoholic fatty liver disease, obesity, diabetes, and environmental toxins (e.g., aflatoxin, chewing of betel quid, and contaminated water). While there are several causes of HCC, etiology is not an independent prognostic factor for HCC; rather, the underlying cirrhosis impacts prognosis and treatment decisions. In the United States, most cases of HCC occur in patients with cirrhosis.1A small proportion, approximately 5 percent, of all HCC cases in Western countries occur in patients without cirrhosis. For patients with early-stage HCC without underlying cirrhosis, surgical resection is the preferred treatment and offers a high probability of a cure. The Barcelona Clinic Liver Cancer (BCLC) guidelines recommend hepatectomy for patients with a single lesion less than 5 cm in size and mild or no underlying cirrhosis. In contrast, patients with severe cirrhosis are not considered resectable and receive supportive care instead. This report focuses on the approximately 80 percent of patients who are not surgical candidates due to advanced-stage disease at diagnosis, inadequate hepatic reserve to tolerate resection, tumors in unresectable locations, or medical comorbidities that result in a high surgical risk. The following are the Key Questions (KQs) addressed in this review. KQ1. What is the comparative effectiveness of the various liver-directed therapies in patients with HCC who are not otherwise candidates for surgical resection or transplantation with no evidence of extrahepatic disease regarding survival and quality of life? KQ2. What are the comparative harms of the various liver-directed therapies in patients with HCC who are not otherwise candidates for surgical resection or transplantation with no evidence of extrahepatic disease regarding adverse events? KQ3. Are there differences in comparative effectiveness of various liver-directed therapies in patients with HCC who are not otherwise candidates for surgical resection or transplantation for specific patient and tumor characteristics, such as age, gender, disease etiology, and Child-Pugh score?