The extent to which T-cell–mediated immune surveillance is impaired in human cancer remains a question of major importance, given its potential impact on the development of generalized treatments of advanced disease where the highest degree of heterogeneity exists. Here, we report the first global analysis of immune dysfunction in patients with advanced hepatocellular carcinoma (HCC). Using multi-parameter fluorescence-activated cell sorting analysis, we quantified the cumulative frequency of regulatory T cells (Treg), exhausted CD4⁺ helper T cells, and myeloid-derived suppressor cells (MDSC) to gain concurrent views on the overall level of immune dysfunction in these inoperable patients. We documented augmented numbers of Tregs, MDSC, PD-1⁺–exhausted T cells, and increased levels of immunosuppressive cytokines in patients with HCC, compared with normal controls, revealing a network of potential mechanisms of immune dysregulation in patients with HCC. In dampening T-cell–mediated antitumor immunity, we hypothesized that these processes may facilitate HCC progression and thwart the efficacy of immunotherapeutic interventions. In testing this hypothesis, we showed that combined regimens to deplete Tregs, MDSC, and PD-1⁺ T cells in patients with advanced HCC restored production of granzyme B by CD8⁺ T cells, reaching levels observed in normal controls and also modestly increased the number of IFN-γ producing CD4⁺ T cells. These clinical findings encourage efforts to restore T-cell function in patients with advanced stage disease by highlighting combined approaches to deplete endogenous suppressor cell populations that can also expand effector T-cell populations. Cancer Res; 73(8); 2435–44. ©2013 AACR.