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The research work was supported by the Spanish Institute of Health Carlos III (COV-20/00792) and by the European Commission - NextgenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global). MAR-H acknowledges support from the Spanish Institute of Health Carlos III and the European Commission - NextgenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global). DC is supported by a predoctoral iPFIS (IFI 19/00048) funded by Spanish Institute of Health Carlos III. MN-N is supported by the Rio Hortega contract (CM20/00074)., IL-6 is one of the major mediators of the hyper-inflammatory responses with complex biological functions as it can signal via different modes of action. IL-6 by classical signalling has anti-inflammatory and antibacterial activities, while trans-signalling mediates proinflammatory effects. The net biological effect of IL-6 is established by multiple factors beyond its absolute concentration. Here, we assess the relationship between IL-6 signalling variables [IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130)] and outcomes in a cohort of 366 COVID-19 patients. The potential trans-signalling was evaluated by a ratio between the pro-inflammatory binary IL-6:sIL-6R complex and the inactive ternary IL-6:sIL-6R:sgp130 complex (binary/ternary complex) and the fold molar excess of sgp130 over sIL-6R (FME). Our data provide new evidence that high levels of IL- 6, sIL-6R, sgp130, binary/ternary complex ratio, and low FME are independent predictors of COVID-19 severity in survivor patients (without death), and the combination of IL-6 + sIL-6R + sgp130 exhibited the most robust classification capacity. Conversely, in a subgroup of patients with a very poor prognosis, we found that high levels of IL-6 and low levels of sIL-6R, sgp130, and binary/ternary complex ratio were predictors of death. In this context, the highest predictive capacity corresponded to the combined analysis of IL-6 + FME + lymphopenia + creatinine. Herein, we present IL-6 signalling variables as a helpful tool for the early identification and stratification of patients with clear implications for treatment and clinical decision-making., Spanish Institute of Health Carlos III (COV-20/00792), European Commission - NextgenerationEU (Regulation EU 2020/2094), CSIC's Global Health Platform (PTI Salud Global), Spanish Institute of Health Carlos III and the European Commission - NextgenerationEU (Regulation EU 2020/2094), iPFIS (IFI 19/00048) funded by Spanish Institute of Health Carlos III, Rio Hortega contract (CM20/00074)