Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Syarifah Ambami Rato Ebu General Hospital, Bangkalan, East Java, Indonesia Background The use of unfractionated heparin (UFH) has been renowned to reduce mortality in COVID-19. There are no data about the efficacy and safety of fondaparinux (FPX) in COVID-19. Purpose To evaluate the efficacy and safety of FPX as compared to UFH in patients hospitalised with severe COVID-19 and coagulopathy. Methods This was a single-center, open-label, equally randomised, parallel-group study conducted between April 1st and July 15th, 2021. Eligible and consenting patients were randomly assigned (1:1 ratio) to receive either FPX or UFH, in prophylactic and therapeutic dose. The primary efficacy endpoint was 28-day all-cause mortality; and secondary efficacy endpoints were episode of acute myocardial infarction (MI), objectively confirmed venous (VTE) or arterial thromboembolism (ATE), progression to non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV), progression to ARDS, sepsis, acute kidney injury (AKI) and acute lung oedema (ALO). The primary safety endpoint was major bleeding (MB); and secondary safety endpoint was clinically relevant non-major bleeding (CRNMB). All composite endpoints were analysed on a 28-day intention-to-treat basis. All patients received guideline-driven therapy throughout the study. Results During allocated period, 250 (71%) of 352 patients were eligible and were assigned to either FPX or UFH group. The baseline characteristics were well-matched between the two groups (all p > 0.05). FPX compared with UFH revealed no significant difference in 28-day all-cause mortality (35.2% vs. 39.2%, hazard ratio HR 0.88, p = 0.59). FPX exhibited no significant difference in the trend of thromboembolic events i.e. acute MI (16.8% vs. 16.8%, HR 0.78, p = 0.53); VTE (2.4% vs. 3.2%, HR 0.49, p = 0.42); and ATE (1.6% vs. 1.6%, HR 0.94, p = 0.95) compared to UFH. Among those not on NIV or IMV at randomisation, FPX showed no significant difference in the proportion of patients meeting the composite endpoint of progression to NIV/IMV (33.6% vs. 35.2%, HR 0.91, p = 0.74) or ARDS (25.6% vs. 24.8%, HR 0.91, p = 0.77). FPX group demonstrated no significant difference in the progression to septic shock (24% vs. 24.8%, HR 0.97, p = 0.92), AKI (19.2% vs. 16%, HR 1.01, p = 0.98), and ALO (10.4% vs. 12%, HR 1.19, p = 0.79) than UFH. Allocation to FPX had no significant effect on the proportion of patients discharged from hospital within 28 days (64% vs. 59.2%, HR 0.72, p = 0.43). Regarding safety, there was no significant difference between FPX and UFH group in terms of major bleeding (1.6% vs. 1.6%, HR 0.88, p = 0.88) or CRNMB (8% vs. 8.8%, HR 0.74, p = 0.53) at 28 days. Our prespecified sub-analysis comparing patients who received the respective therapeutic or prophylactic dose revealed that the efficacy and safety outcomes at 28 days did not differ between the FPX and UFH group (all p > 0.05). Conclusion In patients hospitalised with severe COVID-19 and coagulopathy, FPX was associated with similar efficacy and safety as compared to UFH. Abstract Figure. Baseline characteristics of study groups  Abstract Figure. Allocation of FPX on composite endpoints