Helper T cells are known to mediate hepatic ischemia/reperfusion (I/R) injury. However, the precise mechanisms and subsets of CD4⁺ T cells that contribute to this injury are still controversial. Therefore, we sought to determine the contributions of different CD4⁺ T cell subsets during hepatic I/R injury. Wild-type, OT-II or TCR-deficient mice were subjected to 90 minutes of partial hepatic ischemia followed by 8 hours of reperfusion. Additionally, wildtype mice were pretreated with anti-CD1d, -NK1.1, or -IL-2R antibodies prior to I/R injury. OT-II mice had diminished liver injury compared to wild-type mice, implicating that antigendependent activation of CD4⁺ T cells through TCRs is involved in hepatic I/R injury. TCR-KO mice had decreased hepatic neutrophil accumulation, suggesting that / T cells regulate neutrophil recruitment. We found that NK T (NKT) cells, but not NK cells, contribute to hepatic I/R injury via CD1d-dependent activation of their TCRs, as depletion of NKT cells by anti-CD1d antibody or depletion of both NKT cells and NK cells by anti-NK1.1 attenuated liver injury. Although regulatory T cells (Treg) are known to suppress T cell-dependent inflammation, depletion of Treg cells had little effect on hepatic I/R injury. The data suggest that antigendependent activation of CD4⁺ T cells contributes to hepatic I/R injury. Among the subsets of CD4⁺ T cells, it appears that T cells contribute to neutrophil recruitment and NKT cells directly injure the liver. In contrast, NK cells and Treg have little effects on hepatic I/R injury.