Abstract only Background: SARS-CoV-2 infection potentiates thromboinflammation contributing to poor outcomes in COVID-19. In non-critically ill patients hospitalized for COVID-19, therapeutic-dose heparin improves clinical outcomes. We hypothesized therapeutic-dose heparin impacts thromboinflammatory biomarkers in patients hospitalized for COVID-19 infection. Methods: We conducted a pre-specified secondary analysis of a multi-platform open-label, randomized trial comparing therapeutic-dose versus usual-care thromboprophylaxis-dose heparin in non-critically ill patients hospitalized for COVID-19. Inflammatory markers were analyzed using Wilcoxon rank-sum test and compared based on treatment. Ordinal logistic regression models evaluated for relative D-Dimer change (measured at baseline, day 1, day 3). Odds ratio of a 3-level ordinal outcome (death, survival with organ support, or survival without organ support through 21 days) was determined for relative change. Results: Of 1510 patients, 528 had a D-Dimer on baseline and day 1, and 432 on baseline and day 3. Median age was 60 years (IQR: 50-69) with 41% female and 66% under-represented minorities. Compared to usual-care, therapeutic-dose heparin was associated with a greater drop in D-Dimer at days 1 and 3; other biomarkers were unaffected by treatment (Table 1). D-Dimer at baseline and day 1 had an OR 0.93 (95% CI: 0.88, 0.98) whereas baseline and day 3 had an OR 0.86 (95% CI: 0.78, 0.94) of the ordinal outcome translating in a higher odds of surviving without the need for organ support (adjusted for treatment, gender, and age). Conclusion: In this randomized controlled trial therapeutic-dose heparin was associated with an early reduction in D-Dimer and clinical improvement, suggesting thromboinflammatory mechanisms whereby treatment conferred a clinical benefit. Temporal changes in D-dimer could predict treatment response or may signal need for alternative therapies.