Sorafenib (SO) was the first targeted agent to produce significant improvements in overall survival in patients with advanced hepatocellular carcinoma (HCC). We report the case of a cirrhotic patient with chronic hepatitis C virus infection; locally advanced, unresectable, multinodular HCC, and portal vein tumor thrombosis, who achieved complete tumor regression following SO treatment. The patient was treated with SO 400 mg twice daily, which was subsequently reduced to 200 mg twice daily due to the occurrence of hand-foot skin reaction. The patient also received the following concomitant medications: Synchro-Levels(®) (Alphrema, Varese, Italy), silymarin and vitamin E. Long-term treatment with reduced SO dosage and Synchro-Levels resulted in a sustained radiological and clinical response with normalization of α-fetoprotein levels. Observed side effects were mostly low grade and manageable following dose adjustments. After 44 months of treatment the patient was in good physical condition, which suggests that a complete response with long-term SO is achievable in patients with locally advanced HCC.