BTLA/HVEM (B and T lymphocyte attenuator/herpes virus entry mediator) pathways play a critical role in T cell suppression in tumor. However, its dynamic changes in different T cell subsets in peripheral blood and their clinical significance are largely unclear in cancer patients. In the current study, we showed distinct changes of BTLA and HVEM expressions on peripheral blood CD4(+) and CD8(+) T cells in patients with hepatocellular carcinoma (HCC); BTLA expression were significantly upregulated on circulating CD4(+) but not CD8(+) T cells. In sharp contrast, the levels of HVEM expression were significantly downregulated on circulating CD8(+) but not CD4(+) T cells. A strong positive correlation between BTLA expression on circulating CD4(+) T cells and BTLA expression on autologous CD8(+) counterparts was observed in healthy donors but absent in HCC patients. More importantly, we found that blockade of the BTLA/HVEM pathway increased IFN-gamma production in both circulating CD4(+) and CD8(+) T cells. Collectively, our data suggested that the BTLA/HVEM pathway contributes to peripheral T cell suppression in HCC patients, and BTLA/HVEM may serve as attractive targets for HCC immunotherapy.