Introduction: The main pathophysiological mechanism of the severe form of SARS-CoV-2 infection is the disruption of the immune response with the development of a cytokine storm mediated by the secretion of numerous pro-inflammatory cytokines. Many studies have shown that elevated levels of pro-inflammatory cytokines positively correlate with the outcome of patients with a severe form of SARS-CoV-2 infection. Also, research has shown the mutual impact of COVID-19 and testosterone synthesis disorders. The role of the cytokine TWEAK (TNF-like weak inducer of apoptosis) and its association with testosterone levels and mortality in patients with a severe form of SARS-CoV-2 infection have not yet been investigated. Research objectives: The main aim of the research was to compare the serum levels of TWEAK in the group of patients with a severe form of SARS-CoV-2 infection who survived compared to the group of patients who died. The secondary objectives of the study were to examine the relationship between the serum level of TWEAK and the serum level of testosterone and the risk of mortality in patients with a severe form of SARS-CoV-2 infection. Subjects and methods: 66 men aged 18 to 65 with a diagnosed severe form of SARS-CoV-2 infection who were hospitalized in the Respiratory Intensive Care Center (RIC) between December 2021 and May 2022 were included in the study. Serum levels of testosterone and TWEAK were measured at three time points: the first, seventh and fourteenth days of hospitalization in the RIC. 62 Results: Serum TWEAK levels on the first day of hospitalization in RIC were significantly lower in the group of patients who survived compared to patients who died during hospitalization (179.3 (86.6-375.5) pg/mL vs. 247.2 (89.7-326.8) pg/mL, P=0.037). The serum level of TWEAK on the day of admission to the RIC proved to be a significant predictor of mortality (AUC=0.689, P=0.019) and was negatively correlated with the serum level of testosterone (r= -0.310, P=0.036). The serum level of TWEAK was significantly and positively correlated with the results of the Brixia score scale (r=0.491, P<0.001). Conclusions: Our study showed that serum levels of TWEAK in patients with severe SARSCoV-2 infection were lower in the group of patients who survived compared to patients who died. Serum levels of TWEAK on the day of admission to the RIC proved to be a significant predictor of mortality from a severe form of SARS-CoV-2 infection with a negative association with serum testosterone levels. With the obtained results, we have confirmed the evidence of the role and association of TWEAK and testosterone with the clinical course and outcomes in patients with a severe form of SARS-CoV-2 infection.