This report aims to compare the effectiveness and harms of several local hepatic therapies for unresectable colorectal cancer (CRC) metastases to the liver. In this report, we describe CRC and its diagnosis and treatment to orient the reader to the disease. This is followed by a discussion of the treatment of CRC liver metastasis. CRC is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. It is a cancer that forms in the tissues of the colon and the rectum. Most colorectal cancers are adenocarcinomas, meaning that they are a cancer of the epithelium originating from glandular tissue. Adenocarcinomas develop from adenomas, which are noncancerous tumors in the epithelial tissue. Over time, adenomas can become cancerous. This progression from adenoma to adenocarcinoma occurs through a sequential process of accumulating genetic changes. Although the most common type of CRC is adenocarcinoma, squamous carcinoma and adenosquamous carcinoma have been reported infrequently.An elevated risk of CRC has been associated with obesity, low physical activity, high dietary intake of refined sugars, low dietary intake of fiber, consumption of meat, and consumption of more than two alcoholic drinks per day. A reduction in risk has been linked to the intake of dietary calcium and diets high in fiber and potassium. The objective of this systematic review is to characterize the comparative effectiveness and harms of various local hepatic therapies for liver metastases from unresectable CRC in two distinct patient populations: Patients with unresectable, liver-dominant (i.e., majority of disease located in the liver) metastases who are not eligible for continued systemic chemotherapy because their disease is refractory (i.e., they have experienced disease progression while on therapy); Patients who are candidates for local liver therapies as an adjunct to systemic chemotherapy. There is extensive uncertainty surrounding the optimal use of the various local hepatic therapies. Because of the prevalence of CRC and the high likelihood of metastases, especially to the liver, this topic is important to health care providers, patients, and policymakers. We addressed four Key Questions (KQs) for the two patient populations described above: KQ1. What is the comparative effectiveness of the various liver-directed therapies in patients whose disease is refractory to systemic therapy for unresectable CRC metastases to the liver and who have minimal evidence of extrahepatic disease? KQ2. What are the comparative harms of the various liver-directed therapies in patients whose disease is refractory to systemic therapy for unresectable CRC metastases to the liver and who have minimal evidence of extrahepatic disease? KQ3. What is the comparative effectiveness of the various liver-directed therapies in patients who are candidates for local hepatic therapy as an adjunct to systemic therapy for unresectable CRC metastases to the liver and have no evidence of extrahepatic disease? KQ4. What are the comparative harms of the various liver-directed therapies in patients who are candidates for local hepatic therapy as an adjunct to systemic therapy for unresectable CRC metastases to the liver and have no evidence of extrahepatic disease?