Vitamin K, a cofactor necessary for the production of several antihemorrhagic factors, can inhibit the growth of various types of cells derived from neoplasms. In hepatoma cells, vitamin K2 causes cell-cycle arrest and apoptosis. Vitamin K2 is widely used in Japan to treat osteoporosis. The safety, relatively low cost and ease of use of vitamin K2 have led to good compliance with treatment. The result of preliminary clinical trials in patients with chronic liver diseases are intriguing and suggest that vitamin K2 might reduce the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis as well as prevent disease recurrence after curative therapy in patients with HCC. This article reviews the potential role of vitamin K2 as a chemopreventive agent against HCC and discusses future directions for clinical trials.