Objective Endotoxin is a component of Gram-negative bacteria and can be measured in blood using the endotoxin activity assay (EAA). Endotoxin exposure initiates an inflammatory cascade that may contribute to organ dysfunction. Endotoxemia has been reported in previous viral pandemics and we investigated the extent of endotoxemia and its relationship to outcomes in critically ill patients with COVID-19. Materials and Methods We conducted a Prospective Cohort Study of 96 critically-ill COVID-19 patients admitted to the George Washington University Hospital ICU from 25 Mar-6 Jun 2020. EAA and inflammatory markers (ferritin, d dimer, IL-6, CRP) were measured on ICU admission and at the discretion of the clinical team. Clinical outcomes (mortality, LOS, need for renal replacement therapy (RRT), intubation) were measured. Statistical analysis was conducted using descriptive statistics and effect estimates with 95% confidence intervals. Comparisons were made using chi-square tests for categorical variables, and T-tests for continuous variables. Results A majority of patients (68.8%) had high EAA [≥ 0.60], levels seen in septic shock. Only 3 patients had positive bacterial cultures. EAA levels did not correlate with mortality, higher levels were associated with greater organ failure (cardiovascular, renal) and longer ICU LOS. Among 14 patients receiving RRT for severe AKI, one had EAA < 0.6 (p = 0.043). EAA levels did not directly correlate with other inflammatory markers. Conclusions High levels of endotoxin activity were found in a majority of critically-ill COVID-19 patients admitted to the ICU and were associated with greater risk for cardiovascular and renal failure. Further investigation is needed to determine if endotoxin reducing strategies are useful in treating severe COVID-19 infection.