Prevention is the only realistic approach for reducing mortality rates associated with hepatocellular carcinoma (HCC) worldwide. Vaccination against hepatitis B and screening of blood donations are effective measures of primary prevention. Screening of blood donations has led to a substantial reduction in viral hepatitis transmission among the general population, and in Taiwan vaccination against hepatitis B caused a significant reduction in HCC incidence among infants. Primary prevention also includes approaches that alter epigenetic and genetic changes in hepatocytes, known to increase susceptibility to HCC, as well as treatments slowing progression to cirrhosis. The only evidence that chemoprevention reduces HCC risk is a multicenter randomized prospective study in Asian patients with advanced hepatitis B who received the oral nucleoside analogue lamivudine. Circumstantial evidence suggests that HCC risk is also reduced in patients with chronic hepatitis C who have had a sustained virological response to interferon therapy. HCC is not substantially reduced in patients with hepatitis B treated with interferon and patients with hepatitis C who did not respond to interferon. Secondary prevention, that is, prevention of tumor recurrence after hepatic resection or local ablative therapies, has been pursued with different approaches. Retinoids, hepatic embolization with (131)I lipiodol, and adoptive adjuvant immunotherapy have yielded encouraging results. Other approaches, including those based on interferon alfa or beta, provided inconclusive evidence for secondary prophylaxis of HCC, mainly because of the poor methodologies and scientific background of the studies. Dietary interventions and antiaflatoxin agents might help to prevent HCC in susceptible individuals, but the real efficacy of these approaches is far from being demonstrated.