Although the number of cases and mortality of COVID-19 are seemingly declining, clinicians endeavor to establish indicators and predictors of such responses in order to optimize treatment regimens for future outbreaks of SARS-CoV-2 or similar viruses. Considering the importance of aberrant immune response in severe COVID-19, in the present study, we aimed to explore the dynamic of serum TNF-like weak inducer of apoptosis (TWEAK) levels in critically-ill COVID-19 patients and establish whether these levels may predict in-hospital mortality and if TWEAK is associated with impairment of testosterone levels observed in this population. The present single-center cohort study involved 66 men between the ages of 18 and 65 who were suffering from a severe type of COVID-19. Serum TWEAK was rising during the first week after admission to intensive care unit (ICU), whereas decline to baseline values was observed in the second week post-ICU admission (p = 0.032) but not in patients who died in hospital. Receiver-operator characteristics analysis demonstrated that serum TWEAK at admission to ICU is a significant predictor of in-hospital mortality (AUC = 0.689, p = 0.019). Finally, a negative correlation was found between serum TWEAK at admission and testosterone levels (r = -0.310, p = 0.036). In summary, serum TWEAK predicts in-hospital mortality in severe COVID-19. In addition, inflammatory pathways including TWEAK seem to be implicated in pathophysiology of reproductive hormone axis disturbance in severe form of COVID-19.