The presence of lymphocyte infiltration in human hepatocellular carcinoma (HCC) is evident. However, immune regulation of lymphocytes in HCC is poorly characterized. In this study, we investigated the chemokine receptor and memory, activation and adhesion markers of major leukocyte subsets present in tumor, nontumor liver, and peripheral blood. T cells from both tumor and peritumor liver displayed high levels of activation and homing markers. CCR5 and CXCR3 were expressed in a large proportion of CD45RO+, CD69+, CD27+, and CD11a+ T cells from tumor compared with T cells from circulation. The proportion of CCR6- and CXCR3-expressing natural killer cells (NK) and natural killer T cells (NKT) was significantly increased in the tumor and nontumor liver compared with peripheral blood. This study demonstrates the role of chemokine receptors in the recruitment of specific lymphocyte subsets to the liver in HCC and suggests the importance of these receptors in regulation of immune defense against HCC.