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Background CD4+ regulatory T-cells (Tregs) expand during chronic hepatitis B virus (HBV) infection and inhibit antiviral immunity, although the underlying mechanism remains largely elusive. Myeloid-derived suppressor cells (MDSC) have been linked with T-cell dysfunction but questions remain regarding their persistence/profile/function in chronically HBV infected patients. Aim To characterise MDSC in different phases of chronic HBV infection namely, immune-tolerant (IT), hepatitis B e-antigen-positive chronic hepatitis B (EP-CHB), inactive carriers (IC) and hepatitis B e-antigen-negative chronic hepatitis B (EN-CHB), to investigate their role in Treg induction and evaluate the effect of anti-viral therapy on these cells. Methods Multiparametric flow cytometry, cell-sorting and co-culture assays were performed along with longitudinal immune monitoring of CHB patients receiving tenofovir. Results HLA-DR- CD11b+ CD33hi -Monocytic-MDSC (M-MDSC) were enhanced in IT, EP-CHB and EN-CHB compared with IC, and this was related to increasing hepatitis B surface antigen (HBsAg) concentration. IT and EP-/EN-CHB displayed elevated frequency of CD4+ CD25+ FOXP3+ Treg that positively correlated with that of M-MDSC. However, both M-MDSC and HLA-DR- CD11b+ CD33low -granulocytic-MDSC from IT and EP-/EN-CHB expressed high transforming growth factor beta (TGF-β) and interleukin-10 (IL-10). Co-culture of sorted HLA-DR- CD33+ -MDSC with autologous MDSC depleted-PBMC from IT and CHB but not from IC, increased CD4+ CD25+ FOXP3+ -iTreg and CD4+ FOXP3- IL-10+ -Tr1-cells through a cell-contact independent mechanism. While MDSC-derived TGF-β and IL-10 promoted development of iTreg, only IL-10 appeared to be crucial for Tr1 induction. One year of tenofovir treatment failed to normalise MDSC frequency/function or reduce Treg percentage and serum HBsAg levels, despite reduction in viral load. Conclusions We established a previously unrecognised role of MDSC in Treg development in IT and EP-/EN-CHB via TGF-β/IL-10-dependent pathways and both cell-types persisted after anti-viral therapy. Hence, therapeutic targeting of MDSC or reducing circulating HBsAg level together with tenofovir-therapy might be more effective in restricting HBV persistence and disease progression.