The bone marrow of low risk myelodysplastic syndromes is often associated with an inflammatory environment and active cellular immune response. An active immune response generally contributes to anti-tumor responses and may prevent disease progression. However, chronic immune stimulation can also induce cell stress, DNA damage and contribute in the pathogenesis of myelodysplastic syndromes. Characterizing the protective mechanisms against excessive immune activation is therefore an important aspect of the pathophysiology and may help us to better understand the fine balance between protective and destabilizing inflammation in lower risk disease. In this study we have investigated the role of thrombomodulin (CD141/BDCA-3) expression, a molecule with anti-inflammatory properties, on monocytes in the bone marrow and peripheral blood of myelodysplastic syndrome patients within different risk group. Patient-derived classical monocytes show high expression levels of thrombomodulin, whereas monocytes from healthy donors hardly expressed any thrombomodulin. The presence of thrombomodulin on monocytes from myelodysplastic syndrome patients correlated with lower risk disease groups and a better overall and leukemia-free survival. Using multidimensional mass cytometry (CyTOF), in an in-vitro setting, we show that thrombomodulin positive monocytes could polarize naive T cells toward cell clusters which are closer to Th2 and Treg phenotypes and less likely to contribute in an effective immune-surveillance. In conclusion, the expression of thrombomodulin on classical monocytes is a favorable and early prognostic marker in patients with low risk myelodysplastic syndromes and may represent a new mechanism in the protection against disproportionate immune activation.