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Aim Myeloid-derived suppressor cells (MDSC) can be induced or expanded in tumor-bearing mice and cancer patients. The frequency of MDSC denoted here as Lin−/lowCD33+HLA-DR− was investigated in hepatocellular carcinoma (HCC) patients. The clinical relevance of MDSC and patients' characteristics were examined. Also, MDSC-related immune regulatory pathways in these patients were discussed. Methods The quantity of MDSC was tested in peripheral blood of patients with HCC (n = 63) and healthy donors (n = 56). The expressions of interferon (IFN)-γ, vascular endothelial growth factor (VEGF), cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-13, nitric oxide synthase (NOS)-2 and arginase (ARG)-1 were analyzed. Co-culturing with anti-CD3/CD28-stimulated T lymphocytes was used to determine the suppressive effect of MDSC on the T lymphocytes. Results Patients with treatment-naive HCC had an increased subpopulation of Lin−/lowCD33+HLA-DR− cells in the peripheral blood mononuclear cells (PBMC) with characteristics of MDSC and associated to the stage (P = 0.0004). Patients with splenomegaly had a higher frequency of circulating MDSC. Also, COX-2, MMP-13 and VEGF were expressed differently associated with the alteration of MDSC. Conclusion Our study provides evidence showing an increased population of Lin−/lowCD33+HLA-DR− MDSC in the peripheral blood of HCC patients. Our data also suggest that MMP-13 and COX-2 in PBMC may play a new important role companied with MDSC in HCC patients.