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Although immunotherapy targeting programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway is being applied in clinic, the response outcomes are heterogeneous, suggesting existences of distinctive subsets within PD-1-expressing T cells that react differently to PD-1/PD-L1 blockade. However, markers to demarcate these subsets in human cancers remain unclear. Here, we found that both PD-1 and B and T lymphocyte attenuator (BTLA) were significantly upregulated on CD4 + T cells from tumor compared with those from paired non-tumor liver in hepatocellular carcinoma (HCC) patients. Interestingly, over 85% BTLA + CD4 + T cells were PD-1-expressing cells and represented about 50% PD-1 + CD4 + T cells in tumors, and that level of BTLA + PD-1 + tumor CD4 + T cells were selectively associated with advanced stage HCC. BTLA + identified highly dysfunctional PD-1-expressing CD4 + T cell subset, whereas BTLA - defined PD-1 + CD4 + T cells undergoing activation in HCC. Importantly, blockade of PD-L1 could restore the ability of IFNγ/TNF-α production in BTLA + PD-1 + tumor CD4 + T cells but partially suppressed the activation of BTLA - PD-1 + CD4 + T cells. Moreover, we provided evidence that BTLA signals also participated in suppressing CD4 + T cell function in HCC. In conclusion, BTLA could identify distinct function of PD-1 expressing CD4 + T cells in human cancer, which might not only advance our understanding of inhibitory receptor blockade, but also provide new targets for clinical predictors of response to these immunotherapies.