Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. HCC-induced immunosuppression often leads to ineffectiveness of immuno-promoting therapies. Currently, suppressing the suppressors has become the potential strategy for cancer immunotherapy. So, figuring out the immunosuppressive mechanisms induced and employed by HCC will be helpful to the design and application of HCC immunotherapy. Here, we identified one new subset of human CD14⁺CTLA-4⁺ regulatory dendritic cells (CD14⁺DCs) in HCC patients, representing ∼13% of peripheral blood mononuclear cells. CD14⁺DCs significantly suppress T-cell response in vitro through interleukin (IL)-10 and indoleamine-2,3-dioxygenase (IDO). Unexpectedly, CD14⁺DCs expressed high levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1, and CTLA-4 was found to be essential to IL-10 and IDO production. So, we identified a novel human tumor-induced regulatory DC subset, which suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production, thus indicating the important role of nonregulatory T-cell-derived CTLA-4 in tumor-immune escape or immunosuppression. Conclusions: These data outline one mechanism for HCC to induce systemic immunosuppression by expanding CD14⁺DCs, which may contribute to HCC progression. This adds new insight to the mechanism for HCC-induced immunosuppression and may also provide a previously unrecognized target of immunotherapy for HCC.