Hepatocellular carcinoma (HCC) remains a common cancer worldwide that lacks effective chemoprevention or treatment. Chronic liver disease often leads to impaired hepatic S‐adenosylmethionine (SAMe) biosynthesis, and mice with SAMe deficiency develop HCC spontaneously. SAMe is antiapoptotic in normal hepatocytes but proapoptotic in cancerous hepatocytes. The present study investigated SAMe's effectiveness in prevention and treatment of HCC. Two weeks after injecting 2.5 million H4IIE cells into the liver parenchyma of ACI rats, they typically form a 1‐cm tumor. When SAMe (150 mg/kg/day) was delivered through continuous intravenous infusion, hepatic SAMe levels reached 0.7 mM (over 10‐fold) 24 hours later. This regimen, started 1 day after injecting H4IIE cells and continued for 10 days, was able to reduce tumor establishment and growth. However, if intravenous SAMe was started after HCC had already developed, it was ineffective in reducing tumor growth for 24 days. Although plasma SAMe levels remained elevated, hepatic SAMe levels were minimally increased (30% higher). Chronic SAMe administration led to induction of hepatic methyltransferases, which prevented SAMe accumulation. To see if SAMe's preventive effect on tumor establishment involves angiogenesis, the effect of SAMe on angiogenesis genes was studied. SAMe treatment of H4IIE cells altered the expression of several genes with the net effect of inhibiting angiogenesis. These changes were confirmed at the protein level and functionally in human umbilical vein endothelial cells. Conclusion: SAMe is effective in preventing HCC establishment but ineffective in treating established HCC because of induction of hepatic methyltransferases, which prevents SAMe level to reach high enough to kill liver cancer cells. SAMe's chemopreventive effect may be related to its proapoptotic action and its ability to inhibit angiogenesis. (HEPATOLOGY 2009.)