In recent years, multipotent mesenchymal stromal (stem) cells (MMSCs) were identified and isolated from many tissues and their immunoprivilege and immunosuppressive potential, along with high proliferative activity and multilineage differentiation, have been demonstrated. At the same time, there is an increasing body of evidence of the MMSC plasticity due to a wide range of microenvironmental factors: extracellular matrix, cell-to-cell interactions, oxygen tension, etc. In this study, direct cell-to-cell and paracrine effects of MMSCs on human phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells (MNCs) at the standard (20%) and reduced (5%) O₂ concentrations in the culture medium have been compared. It has been shown that coculture with MMSCs decreases the proliferative activity of PHA-MNCs, the proportion of HLA-DR⁺ T cells, and the interleukin (IL)-6, IL-8, and tumor necrosis factor α (TNF-α) concentrations, and increases the IL-10 and interferon γ (IFN-γ) in the medium. A potentiating effect of low oxygen tension on the immunomodulating properties of MMSCs has been observed, which is of great importance to enchance immunosuppression.