The administration of concanavalin A (Con A) induces a rapid severe injury of hepatocytes in mice. Although the Con A–induced hepatitis is considered to be an experimental model of human autoimmune hepatitis, the precise cellular and molecular mechanisms that induce hepatocyte injury remain unclear. Here, we demonstrate that Vα14 NKT cells are required and sufficient for induction of this hepatitis. Moreover, interleukin (IL)-4 produced by Con A–activated Vα14 NKT cells is found to play a crucial role in disease development by augmenting the cytotoxic activity of Vα14 NKT cells in an autocrine fashion. Indeed, short-term treatment with IL-4 induces an increase in the expression of granzyme B and Fas ligand (L) in Vα14 NKT cells. Moreover, Vα14 NKT cells from either perforin knock-out mice or FasL-mutant gld/gld mice fail to induce hepatitis, and hence perforin–granzyme B and FasL appear to be effector molecules in Con A–induced Vα14 NKT cell–mediated hepatocyte injury.