Abstract Background During severe and critical COVID-19, therapeutic options remain scarce. Among interventions, the use of interleukin-6 receptor inhibitor (IL-6Ri) is especially controversial due to persistent uncertainty about their efficacy and safety. Methods We conducted a multicentric retrospective French observational study. All severe or critical COVID-19 requiring hospital admission were included from march 1 st 2020 to December 31 th 2021. Our main aim was to compare the occurrence of secondary infections function of the administration of IL-6Ri. Digestive, hematological complications and survival were also analyzed. Results Among 2587 patients requiring hospital admission, 1603 had a severe COVID-19 and 984 a critical one requiring ICU admission. 224 received at least one dose of tocilizumab or sarilumab. Incidence of secondary infection was 29.5% in the IL-6Ri group vs. 19.5% without IL-6Ri (unadjusted OR: 1.73 [1.27;2.34]; p = 0.0004) in the whole population. This result remained consistent after adjustment, without multiple imputation (MI) (adjusted OR: 2.12 [1.51; 2.97]; p < 0.0001) and after MI (adjusted OR: 1.47 [1.25; 1.72]; p < 0.0001)). Incidence of hematological or digestive complication were similar between groups. Mortality of patients admitted in ward was higher in the IL-6Ri group (18.7% vs 10.5%, p = 0.0155). No difference in 28 days, ICU, hospital of 90 days mortality was noticed among ICU patients. Conclusion in this population, administration of IL-6Ri was associated with a higher risk of secondary infection in the whole population and with a higher mortality among patients who spent their whole stay in ward.