Abstract RATIONALE: Venous thromboembolism (VTE) frequently complicates sepsis, which incites inflammation and vascular activation. VTE was reported to be highly prevalent in patients critically ill with sepsis due to SARS-CoV-2 (COVID-19). We conducted this study to determine the risk factors for VTE during sepsis and to test whether the incidence was higher in sepsis patients with COVID-19 compared to their non-COVID counterparts. METHODS: We analyzed a single-center cohort of critically ill patients with sepsis prospectively enrolled between April 2015 and January 2024. Eligibility required strongly suspected or confirmed infection and acute organ failure consistent with sepsis-3 criteria. To determine VTE, we searched all clinically-obtained vascular ultrasound and chest computed tomography angiography studies occurring from 5 days before until 14 days after ICU admission for key terms including ‘thromb’, ‘embol’, ‘clot’ and pattern-matched results for VTE diagnosis or lack thereof. COVID-19 was classified by positive polymerase chain reaction or rapid COVID test. We used multivariable logistic regression to test the association between COVID and VTE accounting for covariates previously associated with VTE: early receipt of invasive ventilation or vasopressors, presence of a central venous catheter, history of solid malignancy, and thrombocytopenia. RESULTS: Of the 3,243 enrolled patients, 235 (7.2%) were diagnosed with VTE: 120 (3.7%) with deep vein thrombosis (DVT), 125 (3.9%) with pulmonary embolus (PE), and 10 (<1%) with both. Approximately 10% of the population (306 participants) had sepsis due to COVID-19, with a VTE rate of 10% (31/306). In multivariable adjusted analysis, COVID-19 was an independent risk factor for VTE (OR 1.54, 95% CI 1.02 – 2.33), p=0.042. Other factors associated with higher severity of illness, including receipt of vasopressors, invasive ventilation, and a central catheter were more common in the VTE group though these associations did not independent association in adjusted analysis (Table). CONCLUSION: In critically ill patients with sepsis, VTE was diagnosed more frequently in COVID-19 sepsis than non-COVID sepsis. Our study was conducted at a single health system, and our COVID population sample size was modest. We did not screen for VTE and relied on clinical detection. We acknowledge death as a competing risk that might influence results. COVID sepsis may pose a higher risk for VTE development compared to other sepsis etiologies although clinical trials have not demonstrated a benefit of therapeutic anticoagulation in this population.