AbstractMolecules of the tumour necrosis factor superfamily (TNFSF) are key players in immune regulation; an increase in some TNFSF molecules has been reported during severe COVID‐19. In this study, we profiled and evaluated TNFSF members in the serum of COVID‐19 vaccine‐naïve patients to identify potential biomarkers associated with disease severity. Our data show that TRAIL serum levels are lower in severely affected patients than those mildly affected by COVID‐19 (AUC 0.8, p = 0.0003). On the contrary, OPG and BAFF serum levels are higher in severe COVID‐19 compared to mild COVID‐19 cases (AUC 0.8, p = 0.0001; AUC 0.7, p = 0.0012; respectively) and moderate COVID‐19 cases (OPG p < 0.01), BAFF (p < 0.05). At the transcriptional level, TRAIL, OPG and BAFF are elevated in severe compared to mild COVID‐19 cases, with OPG and BAFF also higher in moderate compared to mild COVID‐19 patients. Additionally, we found that APRIL, LIGHT, CD30L and CD40L protein‐levels are higher in COVID‐19 patients compared to healthy donors but not significantly different between various COVID‐19 clinical statuses. Finally, we found that TNF‐α, TNF‐β, RANKL and TWEAK protein levels were not affected during COVID‐19. Our work identifies OPG and BAFF as potential biomarkers and therapeutic targets for preventing severe COVID‐19. Due to the opposite contradictory levels of TRAIL (protein/transcriptional level), its role during COVID‐19 should be elucidated and clarified with more in‐depth studies.