Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and seventh in women, accounting for 7 % of all cancers, and the third cause of cancer-related death worldwide. Nearly 90 to 95 % of all HCC occur in the context of known and often preventable risk factors, such as chronic viral hepatitis, alcohol abuse, and metabolic disorders. Although several experimental lines of research support a direct role for hepatitis C virus (HCV) in cancer promotion, cirrhosis is the main risk factor for this tumor, whereas other factors like alcohol and tobacco smoking are clearly able to accelerate HCC development. For this reason, cirrhotic patients with chronic HCV infection are subjected to abdominal ultrasound surveillance every 6 months, aimed at an early diagnosis of HCC to allow curative treatment options. Current strategies to positively impact on HCC incidence rates in HCV patients include prevention of cirrhosis development by avoiding metabolic, pharmacological, or social factors associated with accelerated progression of liver disease, or through virus eradication by interferon-based treatments. Moreover, a successful antiviral treatment has the added benefit of positively impacting on the rate of HCC development also in patients who are already cirrhotic.