Introduction: Multiple Sclerosis (MS) is characterized by a chronic inflammation associated to demyelination of the central nervous system (CNS). Many immune cells recruited in CNS were found playing a key role in disease maintenance or progression, rendering them attractive as therapeutical targets but hardly accessible as predictive biomarkers. Although blood sampling is poorly invasive, data exploring modulations of blood immune cells in MS are scarce because of the previous lack of exhaustive immunophenotyping of the patients. Objectives/Aims: With the rise of high-resolution technologies including mass cytometry (Cytof), broad immunophenotyping of patients is now accessible and we used well characterized RRMS samples from the Observatoire Français de la Sclérose en Plaques to perform our study with the aim to define disease biomarkers. Methods: Blood samples of newly diagnosed relapsing remitting (RRMS) patients (n=57), with a clinical and radiological follow up of 24 months were processed by Cytof with a panel of 33 antibodies, compared to sex and age matched healthy controls (HC) (n=26). Results: Significant enrichment of RRMS blood with a peculiar classical monocyte subset (mean HC= 0.153% of myeloid cells vs RRMS= 3.23%; p=0.0061) while non-classical monocytes were found less abundant (mean HC=2.54% of myeloid cells vs RRMS=1%; p<0.0001) was demonstrated by 2 different analysis pipeline. Although circulating, these RRMS-enriched monocytes were expressing both pro- (CCR5, CD86, and S100A9) and anti- (CD206, CD209) inflammatory markers, classically decorating tissue macrophages. Further, this cluster differential abundance was driven by a group of individuals representing 20% of RRMS patients displaying high frequencies of these CD206+CD209+ CCR5+ classical monocytes (over 2% of myeloid cells). These patients were significantly more prone to present an active disease and to develop higher disability score, suggesting a role of this immune population in RRMS disease course. Conclusions: Altogether this study demonstrates that mass cytometry allows the discovery of subtle changes within blood immune compartment able to distinguish RRMS patients from HC and to segregate RRMS patients according to their outcome. This strategy may therefore be used to define new biomarkers of patient outcome and thus to help in treatment choice.