Hepatocellular carcinoma (HCC) is one of the most common solid organ malignancies worldwide, and its incidence is rising in industrialized nations. Sorafenib, an oral multikinase inhibitor, is effective for the treatment of advanced HCC, and is the only systemic drug indicated for the treatment of unresectable HCC. Patients with HCC often have cirrhosis due to viral infection, chronic alcohol consumption, or other causes of liver damage, resulting in reduced liver function of variable severity. Because of the heterogeneity of HCC cases, physicians must consider the benefits and risks associated with sorafenib treatment on a patient-by-patient basis. California Pacific Medical Center (PMC) has established a clinical protocol, discussed here, for treatment of HCC with sorafenib, and for management of treatment-associated adverse effects. In addition, 3 case reports are presented as examples of the use of sorafenib in patient populations not represented in the phase 3 trials: as an adjuvant treatment after a surgical procedure and as effective treatment for stabilizing recurrent and metastatic HCC.