Murine intrahepatic lymphocytes (IHL) are dominated by invariant TCR α-chain expressing CD1d-reactive NKT cells, which can cause model hepatitis. Invariant NKT (CD56+/− CD161+) and recently identified noninvariant CD1d-reactive T cells rapidly produce large amounts of IL-4 and/or IFN-γ and can regulate Th1/Th2 responses. Human liver contains large numbers of CD56+ NKT cells but few invariant NKT. Compared with matched peripheral blood T cell lines, primary IHL lines from patients with chronic hepatitis C had high levels of CD161 and CD1d reactivity, but the invariant TCR was rare. CD1d-reactive IHL were strikingly Th1 biased. IHL also demonstrated CD1d-specific cytotoxic activity. Hepatocytes and other liver cells express CD1d. These results identify a novel population of human T cells that could contribute to destructive as well as protective immune responses in the liver. CD1d-reactive T cells may have distinct roles in different tissues.