Background and purpose: While HCC is an inflammation-associated cancer, CRLM develop on permissive healthy liver microenvironment. To evaluate the immune aspects of these two different environments, peripheral blood-(PB), peritumoral-(PT) and tumoral tissues-(TT) from HCC and CRLM patients were evaluated. Methods: 40 HCC and 34 CRLM were enrolled and freshly TT, PT and PB were collected at the surgery. PB-, PT- and TT-derived CD4+CD25+ Tregs, M/PMN-MDSC and PB-derived CD4+CD25− Teffector cells (Teffs) were isolated and characterized. Tregs function was also evaluated in the presence of the CXCR4 inhibitor, Peptide-R29, AMD3100 or anti-PD1. RNA was extracted from PB/PT/TT-tissues and tested for FOXP3, CXCL12, CXCR4, CCL5, IL-15, CXCL5, Arg-1, N-cad, Vim, CXCL8, TGFβ and VEGF-A expression. Results: In HCC/CRLM-PB higher number of functional Tregs, CD4+CD25hiFOXP3+ were detected, although PB-HCC Tregs exert a more suppressive function as compared to CRLM-Tregs. In HCC/CRLM-TT Tregs were highly represented with Activated/ENTPD-1+Tregs prevalent in HCC. As compared to CRLM, HCC overexpressed CXCR4 and N-cadherin/Vimentin in a contest rich of arginase and CCL5. Monocytic-MDSCs were highly represented in HCC/CRLM while high Polymorphonuclear-MDSCs were detected only in HCC. Interestingly, CXCR4-PB-Tregs function was impaired in HCC/CRLM by the CXCR4 inhibitor R29. Conclusion: In HCC and CRLM, peripheral blood, peritumoral and tumoral tissues-Tregs are highly represented and functional. Nevertheless, HCC display a more immunosuppressive TME due to Tregs, MDSCs, intrinsic tumor features (CXCR4, CCL5, arginase) and the contest in which it develops. As CXCR4 is overexpressed in HCC/CRLM tumor/TME cells, CXCR4 inhibitors may be considered for double hits therapy in liver cancer patients.