Sepsis is one of the leading causes of in-hospital mortality. In some patients, sepsis-induced immunosuppression is associated with increased risk of death and secondary infections. In oncology, myeloid-derived suppressor cells (MDSCs) have been described to inhibit various immune functions. Monocytic MDSCs (M-MDSCs) represent a subtype of MDSCs. The objectives of the present study was to determine by flow cytometry the % M-MDSCs (among total monocyte population) in a cohort of septic shock patients and to assess its association with deleterious outcomes: 28-day mortality and occurrence of nosocomial infections. The cohort included 301 patients. They presented with immune alterations usually found 3-4 days after the onset of shock: lymphopenia (median T CD4: 362/μL, quartiles: 235-591/μL) and low monocytic HLA-DR expression (median: 4,944 AB/C, quartiles: 3,104-8,266 AB/C). From admission until the end of the first week, % M-MDSCs was significantly increased in patients compared with healthy donors (p < 0.01). In early samples, no association with deleterious outcomes was identified. However, after one week, patients who were going to die or to develop nosocomial infections presented with significantly higher % M-MDSCs than non-survivors and non-infected patients (p < 0.01). These associations remained significant in multivariate analyses, odds ratio of 4.4 (p = 0.001) regarding 28-day mortality and 2.4 (p = 0.013) regarding occurrence of nosocomial infections. In conclusion, % M-MDSCs was markedly increased after septic shock. One week-persistence of an increased proportion of M-MDSCs was associated with unfavorable outcomes.