Concanavalin A (ConA), directly injected into mice, induces T cell–mediated liver injury. However, it remains unclear whether ConA injection can activate innate immune cells, including natural killer (NK) cells and natural killer T (NKT) cells, both of which exist abundantly in the liver. Here we report that ConA injection stimulated interferon (IFN)‐γ production from liver NKT cells as early as 2 hours after injection and augmented YAC‐1 cytotoxicity of liver NK cells. ConA‐induced NK cell activation required other types of immune cells and critically depended on IFN‐γ. Because a nonhepatotoxic low dose of ConA was capable of fully activating both NKT cells and NK cells, we next addressed the possibility of ConA injection displaying an antitumor effect in the liver without liver injury. A nonhepatotoxic low‐dose ConA injection augmented the cytotoxicity of liver NK cells against Colon‐26 colon cancer cells and suppressed hepatic metastasis of Colon‐26 cells in a NK cell– and IFN‐γ–dependent manner. In conclusion, a nonhepatotoxic low dose of ConA might serve as an immunomodulator that can preferentially activate the innate immune cells to induce an antitumor effect against metastatic liver tumor. (HEPATOLOGY 2004;40:1190–1196.)